A LobPass Versus a BulletAquarterback can throw a receiver a high, lazy lob pass or a low, quick bullet pass. These passes are indicated by curves 1 and 2, respectively, in Figure 422. (a) The lob pass is thrown with an initial speed of 21.5 m/s and its time of ight is 3.97 s. What is its launch angle? (b)The bullet pass is thrown with a launch angle of 25.0. What is the initial speed of this pass? (c) What is the time of ight of the bullet pass?
1 Endocrine and Neuroendocrine Physiology Chapter 16 Introduction to Endocrine Principles Nervous systems: they are fast and addressed Endocrine system: slower and longer-lasting, broadcast. Red dots are signaling molecules: neurotransmitter molecules in (a) and hormone molecules in (b). (a) Neurons have long axons that rapidly propagate action potentials, and also use short-distance chemical neurotransmitter signaling to communicate from cell to cell. (b) Endocrine cells release chemical hormones into circulatory fluids that carry the hormonal message over long distances to activate hormone receptors on other cells. The nervous system and the endocrine system work in systematically different ways to control and coordinate the cells of an animal. As shown in (a), a signal in a neuron travels electrically along a cell process all the way to its target cell; transmission along the cell process is very fast and spatially highly defined (a signal travels only along the cell process in which it was initiated). When the electrical signal arrives at the end of the neuron process, it causes the release of a chemical substance—a neurotransmitter—that diffuses quickly across the minute gap between the neuron process and the target cell. When this chemical substance arrives at the target cell, it binds (noncovalently) with specific receptor molecules on the cell, activating target-cell responses. In contrast, as shown in (b), when an endocrine cell emits a signal, it does so by secreting a chemical substance—termed a hormone—into the general blood circulation. The signal travels more slowly than a neuronal signal because it is carried by blood flow, but instead of being spatially highly circumscribed, the signal is transmitted to all cells in the body. The target cells—the cells that respond—are the subset of cells that have receptor proteins for the hormone in their cell membranes. What is a hormone Its a chemical substance produced and released by non-neural endocrine cells or by neurons; exerts regulatory influences on the function of other distant cells reached via the blood; effective at low concentrations. 2 In Chapter 12 we compared rapid, “addressed” neural control of physiological processes with slow, “broadcast” endocrine control. Chemical signals are used to achieve both types of control. However, in neural control, neurotransmitters released from axon terminals of neurons diffuse short distances to bind to receptor molecules on postsynaptic cells (Figure 16.1a). Their short travel time to discrete sites ensures rapid, pin-pointed control. Enzymes or reuptake mechanisms rapidly inactivate most neurotransmitters, so the neural signal is quickly terminated. By contrast, hormones secreted from endocrine or neuroendocrine cells travel in the blood to distant target cells where they exert their effects (Figure 16.1b,c). Whereas neurotransmitter molecules from an axon terminal typically reach a single postsynaptic cell, hormone molecules carried through the bloodstream can influence large populations of target cells, as long as the target cells express receptor molecules for the hormone. Therefore, transport of hormones over long distances permits widespread responses. These responses are initiated slowly, relative to responses to neural signals, because hormones require travel time to reach target cells. Further, some hormones are synthesized only when the endocrine cell is stimulated to secrete them, and this synthesis takes time. Finally, certain hormones control gene transcription and the synthesis of proteins by target cells, so the responses they initiate are exhibited only after a delay, when protein synthesis is accomplished. Responses to hormones may be brief or last as long as hours or days. Processes controlled by endocrine systems in both vertebrates and invertebrates include water balance, metabolism, coping with a hostile environment, reproduction, and growth and development. Although researchers have accumulated a great deal of detailed knowledge regarding the functions and roles of hormones in vertebrates, our understanding of the endocrine systems of many invertebrate groups is still highly incomplete. Nevertheless, physiologists have found that the basic principles of endocrine function—our focus in this chapter— 3 apply to both vertebrates and invertebrates. Defined specifically, a hormone is a chemical substance produced and released by non-neural endocrine cells or by neurons; it exerts regulatory influences on the function of other, distant cells reached via the blood; and it is effective at very low concentrations (as little as 1012 M). Hormones released by neurons are often referred to as neurohormones, and the neurons as neuroendocrine or neurosecretory cells. The secretory cells that produce hormones secrete them into the surrounding extracellular fluid, from which they diffuse into capillaries. The secretory cells may be organized into discrete organs termed endocrine glands (also called ductless glands because they lack outflow ducts), or they may be isolated cells or clusters of cells distributed among the cells of other tissues. A table of the major mammalian endocrine and neuroendocrine tissues, their secretions, and their main actions at target tissues can be found in Appendix K. Some substances are unambiguously hormones, such as thyroid hormones (secreted by the thyroid gland) and gastrin (secreted by G cells in the gastric mucosa of the lower part of the mammalian stomach). Many substances carried in the blood— CO , f2r example—may act as signals but are clearly not hormones. CO i2 produced by metabolism and signals the respiratory centers of some animals to increase their breathing. However, CO is 2ot released primarily by specialized secretory cells, and it is found continuously in the blood at relatively high concentrations. Not all compounds, however, are so easily categorized. Many chemical signals affect the function of nearby cells located in the same organ or tissue but do not enter the circulatory system. These autocrine and paracrine substances act in many ways like hormones but are usually categorized separately (Figure 16.1d). Furthermore, the same compound may be used both as a hormone and as another type of chemical signal in the same organism. In mammals, for example, cholecystokinin (CCK) is not only a hormone secreted by cells in the intestine, but also functions as a neurotransmitter or neuromodulator in the central nervous system (CNS). Intracrines are another example of signaling molecules. These peptide growth factors or hormones function within cells in addition to performing traditional hormonal, paracrine, or autocrine functions. Intracrines are either retained within the cell that synthesized them or internalized from the extracellular space. Hormones bind to receptor molecules expressed by target cells Although a hormone circulates past many cells, it interacts only with certain cells, called target cells, that respond to it. A target cell expresses receptor molecules that specifically bind the hormone. Consider thyroid hormones, for example. These hormones, secreted by the thyroid gland, exert a wide range of metabolic, structural, and developmental effects on 4 many different tissues (see Appendix K). They have such widespread effects because many different cells of the body possess receptor molecules that recognize thyroid hormones. Typical target cells express thou- sands of receptor molecules for a particular hormone. In addition, many target cells express separate populations of different types of receptor molecules, so they are capable of responding to more than one hormone. The sensitivity of a target cell to a particular hormone depends on the number of functional receptor molecules the target cell expresses for that hormone. The sensitivity of a target cell to a particular hormone can change under different conditions because the number of receptor molecules that recognize that hormone can increase (by up-regulation) or decrease (by down-regulation). These variations in the types and numbers of receptor molecules expressed by target cells contribute to the immense versatility of hormonal regulation in animals. An additional consideration to keep in mind is that a target cell’s response to a particular hormone at any moment in time depends not only on the number of receptor molecules it expresses for that hormone but also on the hormone’s concentration in the blood. Concentration of hormones in the blood vary For hormones to serve as physiological regulators, their rates of synthesis and secretion must be controlled. Often neurons or other hormones control these processes. Most endocrine cells synthesize and release some hormone all the time, but the rate of release is variable, depending on mechanisms of control. In general, the higher the rate at which a hormone is secreted, the higher its con- centration in the blood, and the greater its effect on target cells. Because hormone molecules secreted into the blood are enzymatically degraded at their targets or by organs (such as the liver and kidneys in vertebrates), they do not circulate indefinitely. The blood concentration of a hormone represents a balance between the rate of addition of hormone to the blood (by secretion) and the rate of removal of hormone from the blood (by metabolic destruction and excretion). Hormone concentration depends primarily on the rate of addition to the blood, because the rate of removal is relatively constant. A hormone’s half-life—the time required to reduce the concentration by one- half—indicates its rate of removal from the blood and thus the duration of its activity. Some hormones may be converted to a more active form after secretion by a process termed peripheral activation. For example, thyroid hormone is secreted mainly as a four-iodine compound also known as tetraiodothyronine, or T . Aft4r T 4s secreted, target and other tissues enzymatically remove one iodine to form triiodothyronine, or T 3 which is more physiologically active than T . 4 5 Most hormones fall into three chemical classes 1. Steroid hormones are synthesized from cholesterol(Figure 16.2). In vertebrates, the gonads and the adrenal cortex secrete steroid hormones, as do the skin and, in pregnant mammals, the placenta. The molting hormonesof arthropods (e.g., ecdysone) are also steroids. Steroid hormones are lipid-soluble, so they can pass through cell membranes to reach receptor molecules located insidetheir target cells. In some cells, lipid-soluble hormones(e.g., estrogen) are transported across the membrane. One transporter of these hormones is megalin, an integral protein receptor molecule of the target cell membrane that brings lipid-soluble hormones (often complexed with carrier molecules) into the cell by endocytosis. 2. Peptide and protein hormones are structured from chainsof amino acids (Figure 16.3). In vertebrates, they include antidiuretic hormones, insulin, and growth hormone. Examples of peptide and protein hormones in invertebrates include the gamete-shedding hormone of sea stars and the diuretic hormones of insects. Peptide and protein hormones vary enormously in molecular size, from tripeptides (consisting of just 3 amino acid residues, suchas thyrotropin-releasing hormone) to proteins containing nearly 200 amino acids (such as growth hormone). Often hormones consisting of assemblages of amino acids are simply called peptide hormones (blurring the size distinction), and we will usually follow that practice. Peptide hormones are soluble in aqueous solutions. 6 3. Amine hormones are modified amino acids (Figure16.4). Melatonin, secreted by the vertebrate pineal gland (see Chapter 15), is derived from tryptophan, whereasthe catecholamines and iodothyronines are derivedfrom tyrosine. Catecholamines are found widely assynaptic transmitter substances in both invertebratesand vertebrates. However, three catecholamines alsoserve as hormones in vertebrates: epinephrine (alsocalled adrenaline), norepinephrine (noradrenaline), and dopamine. Iodothyronines, the thyroid hormones, are found only in vertebrates. They are synthesized by the thyroid gland and have the unique property of being rich in iodine. Whereas melatonin and the catecholamines are soluble in water, the iodothyronines are soluble in lipids. Synthesis, Storage and Release of Hormones 7 Chemical Class of Hormone Determines: Method of transport in blood: Lipid-soluble hormones (steroid hormones and some amine hormones are transported in the blood bound to water soluble carrier proteins. Hormone half-life or how long the hormone remains active: Lipid-soluble hormones bound to carriers remain active longer (1-2 hrs.) than water-soluble peptide hormones (minutes). Mechanism of hormone action: Lipid-soluble hormones can cross membranes to bind to INTRACELLULAR receptors some of which are transcription factors that directly regulate gene expression in the nucleus. Water-soluble hormones bind membrane receptors, many of which are the seven-transmembrane receptors that, when bound, signal through G-proteins. Summary Endocrine Principles Diverse cell types make and release hormones into the blood. The 3 main types of hormones are peptide/protein, steroid, and amines. Half-lives vary, minutes to days, depending on chemistry and carrier mechanism. Target cells express hormone receptors that can impact both second messengers and gene expression. Summary Synthesis, Storage and Release The type of hormone synthesized by an endocrine cell depends on proteins expressed (peptides/proteins) and modifying enzymes (steroids/amines). Peptides/proteins and amines are packaged into vesicles for secretion. Control of Endocrine Secretion: The vertebrate Pituitary gland In this section we use the vertebrate pituitary gland as an example to illustrate two major controls of secretion: neural control of secretion by neurosecretory cells and neurosecretory control of secretion by endocrine cells. The principles of control described in this example also apply to other endocrine tissues in both vertebrates and invertebrates. This section will also demonstrate that, although pituitary secretions exert far-reaching effects, the hypothalamus dominates pituitary gland functions. The pituitary gland lies immediately below the hypothalamus and consists of two parts: the adenohypophysis, commonly called the anterior pituitary, and the neurohypophysis, commonly called the posterior pituitary. In development, the anterior pituitary forms from a dorsal evagination (outpocketing) of the oral cavity called Rathke’s pouch. This completely nonneural tissue pinches off from the oral cavity to associate closely with the posterior pituitary, which is an extension of the hypothalamus. 8 The posterior pituitary illustrates neural control of neurosecretory cells Hypothalamic neurosecretory neurons project to the posterior pituitary where they release peptide hormones Oxytocin and vasopressin (ADH) into blood. The posterior pituitary (neurohypophysis) consists of bundles and terminations of axons that originate in the hypothalamus (Figure 16.6). Hypothalamic neurosecretory cells extend their axons through the median eminence, which forms part of the floor of the hypothalamus, along the infundibular stalk, and into the pars nervosa (“nervous part”), where the axons terminate at a rich network of capillaries. (The posterior pituitary is also called the neural lobe or posterior lobe.) In most mammals, two peptide hormones are released into the blood in the pars nervosa: vasopressin and oxytocin. Vasopressin, also called antidiuretic hormone (ADH), limits the production of urine and also stimulates constriction of arterioles. The functions of oxytocin (which is produced in both males and females) include causing contractions of the uterus during birth and ejection of milk by the mammary glands during suckling. In mammals (see Figure 16.6), two paired clusters of cell bodies in the hypothalamus, the paraventricular nuclei and supraoptic nuclei, are the main sites of production of these two peptides. When the neurosecretory cells are stimulated, they generate action potentials that propagate from the hypothalamus to their axon terminals in the pars nervosa. Here they release hormone by exocytosis into the extracellular fluid near capillaries, and the hormone diffuses into the blood. The hypothalamus–posterior pituitary connection illustrates one form of control of endocrine function: neural control of neuro- secretory cells. The neurosecretory cells that produce and secrete vasopressin and oxytocin receive and integrate synaptic input from a host of typical neurons. Vasopressin cells, for example, receive input about blood volume and the osmotic 9 concentration of body fluids. When they receive signals reporting high osmotic concentration and/or low blood volume, they secrete vasopressin, which triggers processes involved in retaining water. Likewise, oxytocin cells respond to signals from the mammary glands when suckling occurs or from the cervix of the uterus during labor and birth. The anterior pituitary illustrates neurosecretory control of endocrine cells Releasing hormones for examples CRH (Corticotropin Releasing Hormone) are secreted by neurosecretory neurons into capillaries of the median eminence. CRH then triggers endocrine cells in the anterior pituitary to secrete hormones for example ACTH which is Adrenocorticotropic Hormone There are MANY other releasing hormones and pituitary hormones released by the anterior pituitary. The anterior pituitary (adenohypophysis) is nonneural endocrine tissue (Figure 16.7). It is subdivided into the pars distalis, pars intermedia, and pars tuberalis (see Figure 16.6). The exact positions and relative sizes of these parts vary greatly from one animal group to another, and in some groups not all parts are present. All the hormones of the anterior pituitary are synthesized and secreted by endocrine cells within its tissues. Different specific populations of cells secrete different hormones. All anterior pituitary hormones are peptides, proteins, or glycoproteins (proteins with covalently bound carbohydrate chains). Anterior pituitary hormones are categorized into two main groups according to their target tissues. The hormones of one group exert their principal effects on nonendocrine tissues. Growth hormone (GH), for example, influences growth and nutrient metabolism in tissues such as fat and muscle. Other hormones of this group are prolactin and melanocyte-stimulating hormone (MSH). The second group includes hormones that control other endocrine glands. By 10 convention, hormones that influence the functions of other endocrine glands have the suffix -tropic in their names, or are called tropins. Thyroid-stimulating hormone (TSH), for example, is also called thyrotropin. This anterior pituitary hormone supports and maintains the tissues of the thyroid gland and also stimulates the gland to secrete thyroid hormones. If a target gland is deprived of input from its tropic hormone, the gland not only stops secreting hormone, but also shrivels in size. Adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) are also tropic hormones produced by the anterior pituitary. The general functions of the anterior pituitary hormones are listed in Appendix K. HPA axis (Hypothalamus – pituitary – adrenal cortex axis) Secretion by neurosecretory cells: corticotropin-releasing hormone (CRH) into median eminence. CRH stimulates anterior pituitary to produce adrenocorticotropic hormone (ACTH). ACTH released into blood carried to adrenal cortex, stimulates glucocorticoid secretion. Glucocorticoids: blood vessel responses, inflammation. Primates and fish: cortisol Reptiles, birds, amphibians and rodents: corticosterone. The adrenal gland secretes several hormones. Here we limit our consideration to the glucocorticoids (cortisone, cortisol, and corticosterone), a class of steroid hormones so named because (among other functions) they promote an increase in the blood concentration of glucose (“gluco”) and because they are secreted by the adrenal cortex (“cortico”). Glucocorticoids are central to homeostasis. Their widespread effects include ensuring adequate blood glucose levels, maintaining the responsiveness of blood vessels to stimulation by catecholamines, and limiting inflammation. The main glucocorticoid produced in primates and fish is cortisol, whereas in reptiles (including birds), amphibians, and rodents, it is corticosterone. Stressful or challenging conditions cause increased glucocorticoid secretion. (We consider the mammalian stress response later in this chapter). Glucocorticoid secretion is controlled by the HPA axis. Brain neural activity is integrated by neurons that secrete corticotropin-releasing hormone (CRH) into the capillaries of the median eminence. CRH is carried in the portal system to the anterior pituitary, where it stimulates adrenocorticotropic cells to secrete ACTH into capillaries leading to the general circulation. ACTH is carried to the adrenal cortex, where it stimulates gluco- corticoid secretion. Glucocorticoids act at different target tissues to influence many physiological processes. FEEDBACK! 11 Any stage in this control pathway can be modulated. Negative feedback (see Figure 16.10) is the most widespread type of hormonal modulation. In negative feedback, a hormone causes changes in its control pathway that tend to suppress its own secretion. In the HPA axis, high glucocorticoid levels tend to suppress secretion of CRH by the hypothalamus and ACTH by the anterior pituitary, and also to reduce the responsiveness of the ACTH cells to CRH. As a result, the pituitary secretes less ACTH, and the adrenal cortex receives less stimulus to secrete glucocorticoids. Mechanisms of negative feedback do not reduce hormone secretion to zero, but instead serve to stabilize blood concentrations of hormones. Occasionally, hormonal modulation involves positive feedback, such as that resulting in the explosive increase in oxytocin secretion during the process of birth. Interaction of insulin, glucagon and epinephrine illustrate synergism and antagonism between hormones. In addition to feedback mechanisms, other types of hormonal modulation can affect endocrine control pathways. For example, hormones that are ancillary parts of a pathway can alter a target gland’s response to a particular hormone. In the HPA pathway, vasopressin (VP) acts together with CRH to increase the secretion of ACTH from the anterior pituitary. Not all VP-secreting neurosecretory cells in the hypothalamus extend their axons to the posterior pituitary. Some terminate their axons on the capillary bed of the median eminence. When released, VP circulates through the portal vessels to the anterior pituitary. By itself VP has little effect on the ACTH-secreting cells. However, when these cells receive signals from both VP and CRH, their secretion is greater than it would be under the influence of CRH alone. This sort of effect, in which one hormone can amplify the effect of another, is 12 called synergism. A hormone can influence the effects of another hormone at the same target tissue in three different ways: by synergism (producing an enhanced response such as we have seen with VP and CRH), permissiveness (in which the presence of one hormone is required for the other to exert an effect), or antagonism (in which one hormone opposes the action of another). One example of permissiveness is that of cortisol permitting the catecholamines epinephrine and norepinephrine to cause constriction (narrowing of the diameter) of blood vessels, a function necessary to maintain normal blood pressure. Because cortisol must be present for vasoconstriction to occur, basal levels of this glucocorticoid are necessary for homeostatic regulation of blood pressure. Without treatment, humans with a condition called “adrenal insufficiency” (who are unable to secrete adequate amounts of hormones from the adrenal cortex) are at risk of death if they experience a stress, such as a hemorrhage, that requires systemic vasoconstriction. An example of antagonism is the interaction between insulin and glucagon. We know that insulin secreted from Beta cells in the islets of Langerhans in the pancreas promotes uptake of glucose from the blood by many different tissues. Glucagon is a hormone secreted by A, or alpha, cells in the islets, and it functions to oppose the action of insulin: It stimulates the release of glucose and fatty acids into the blood. The balanced actions of these two hormones help maintain stable levels of glucose in the blood. In situations, such as stress, in which higher blood concentrations of glucose are required to respond to a crisis, glucagon secretion increases and insulin secretion decreases. Figure 16.11 shows blood glucose levels in dogs given insulin alone or in combination with glucagon and epinephrine. Epinephrine and glucagon are both antagonists of insulin, and they work synergistically to oppose insulin’s action. The mammalian Stress Response 13 Adaptation allowing for immediate response to challenging situations: wounds, environmental extremes, vigorous exercise, unfavorable social conditions. Intermingled functions of autonomic nervous system (sympathetic “fight or flight” response) and endocrine system (HPA axis) In this section we use the mammalian stress response (Figure 16.12) to illustrate and integrate several of the principles of endocrinology discussed in previous sections. The stress response is an adaptation that allows an animal to respond immediately in a generalized way to a threatening or challenging situation. Stressors experienced by animals include being wounded, being exposed to thermal extremes (birds and mammals) or other hostile environmental conditions, being forced to exercise vigorously, and experiencing troublesome social conditions or high levels of emotion. We tend to think of stressors as negative challenges to survival, but in some instances they may heighten experiences in a positive way. In humans, and perhaps other animals as well, stressors over which an individual perceives a sense of control can be rewarding. For example, seeking novel situations generates stress but also facilitates intellectual and emotional growth. Interestingly, feeding and sexual activity—both essential behaviors for biological success—also stimulate the stress system. During the stress response, heart and breathing rates increase, cognition and 14 alertness are sharpened, metabolic processes release stored energy, oxygen and nutrients are directed to the CNS and to those sites in the body that are stressed the most, and feeding and reproduction are curtailed. All of these changes serve to ensure survival in an acute crisis. Different stressors differentially turn on different components of the stress response; however, any one stressor that is sufficiently potent will turn on a generalized stress syndrome. When the stressor is no longer present, feedback mechanisms ensure that the stress response is turned off. In the classic example of a zebra chased by a lion, the threat is clear, the physiological response is swift, and the episode has a finite end. However, if a stressor (physical or emotional) persists for long periods, physiological responses that are adaptive in the short term become damaging in the long term. Description of the figure The rat detects the cat and runs. Within seconds of the threat, the rat’s sympathetic nervous system releases catecholamines (epinephrine and norepinephrine) from sympathetic nerve terminals and the adrenal medulla, and hypothalamic neurosecretory cells release CRH into the hypothalamo–hypophysial portal system. A few seconds later, the anterior pituitary secretes ACTH. Thus two output systems, the sympathetic “fight-or-flight” system and the HPA axis, together mount the response to a stressor. Their functions are not independent, but intermingled. For example, in addition to its role as a neurohormone that stimulates ACTH secretion, CRH also acts as a neurotransmitter in other areas of the brain, where it stimulates the sympathetic nervous system. Researchers uncovered this additional role of CRH by injecting it into the brain ventricles of dogs and rats whose pituitary glands had been removed. These animals secreted no ACTH, because the ACTH-secreting cells were gone. However, injected CRH caused increases in blood concentrations of catecholamines and associated increases in blood pressure and heart rate. Experiments such as these reveal that one of the functions of CRH is to link the sympathetic and adrenocortical branches of the stress response. CRH also acts as a neurotransmitter or neuromodulator in the amygdala and hippocampus (which function together to form memories of emotionally charged events). The two output branches of the stress response are also linked by norepinephrine. The CRH neurosecretory cells in the hypo- thalamus receive noradrenergic synaptic input from several different nuclei of the brain. Some of these nuclei are innervated by neurons using CRH as their neurotransmitter, so that reciprocal interactions are possible. Like CRH, norepinephrine also provides input to the amygdala and hippocampus. Although researchers understand many CRH and 15 norepinephrine connections in the brain, they do not know what neurocircuitry upstream of these pathways actually turns on the stress response. The stress response includes two phases (see Figure 16.12). First, within less than 1 min, the catecholamines (epinephrine and norepinephrine) trigger increases in heart and respiration rates, blood pressure, and other sympathetic responses. These changes provide increased blood flow to the skeletal muscles and heart, as well as increased air flow into and out of the lungs as the bronchial airways increase in diameter. Blood vessels to the skin constrict, diverting blood from sites of possible injury. Digestive functions are suppressed. Arousal of the CNS and alertness are promoted. Epinephrine stimulates the release of glucose into the blood by triggering the breakdown of glycogen stored in the liver and muscles, and it also stimulates the release of fatty acids from lipid stores. Epinephrine in the blood and norepinephrine from sympathetic nerve terminals both inhibit insulin secretion and stimulate glucagon secretion from the islets of Langerhans. Ordinarily, increased glucose in the blood would stimulate insulin secretion, which would promote the uptake of glucose from the blood by all tissues except brain and exercising skeletal muscle. By inhibiting insulin secretion and stimulating glucagon secretion, the catecholamines ensure plentiful levels of glucose in the blood to fuel physical exertion and maintain brain function. Additional synergies occur during the first phase of the stress response. For example, epinephrine (in addition to CRH) appears to stimulate the secretion of ACTH, and ACTH may do more than stimulate glucocorticoid secretion. ACTH is known to facilitate learning, and it may contribute to an animal’s preparedness in responding to a similar stressor in the future. Finally, ACTH is produced by cleaving of a preprohormone, POMC, and can be co-secreted along with other fragments of POMC, including -endorphin. The latter substance (also produced by POMC cells in the hypothalamus) is an endogenous opiate and may contribute to analgesia; that is, it may decrease the animal’s perception of pain. In the second phase of the stress response (see Figure 16.12), glucocorticoids are secreted by the adrenal cortex. The full effects of glucocorticoids on target tissues can be detected about 1 hour after the stress response is initiated. Glucocorticoids reinforce the actions of the sympathetic nervous system and have additional metabolic effects that facilitate the release of usable sources of energy into the bloodstream. They stimulate the catabolism of protein in muscle and (at high levels) bone, and they stimulate the liver to use the released amino acids to produce glucose in a process called gluconeogenesis. The liver cells release this newly formed glucose into the blood. Like epinephrine and norepinephrine, glucocorticoids oppose the action of insulin and ensure fuel availability. Glucocorticoids also stimulate catabolism of fats so that fatty acids can be used as an alternative energy source by all tissues except the brain (which uses only 16 glucose in the short term but can use ketoacids made from fatty acids in the liver during starvation). The metabolic actions of glucocorticoids, coordinated with those of the catecholamines, ensure glucose availability to the brain in the face of required physical exertion and possible enforced fasting (for example, while hiding from a predator or recovering from a wound). The amino acids released by protein catabolism are also available for tissue repair. In addition to their important metabolic effects, glucocorticoids increase their permissive effect on vasoconstriction stimulated by the catecholamines, as we saw earlier. They also inhibit the secretion of gonadotropins (FSH and LH), thyrotropin (TSH), and growth hormone (GH) from the anterior pituitary. Assuming the chase is short, and, for example, the rat pops into its burrow before the cat seizes it, the inhibitory effects of glucocorticoids on reproduction and growth are minimal. Safe in its burrow, the rat experiences diminished sympathetic neural responses, and the glucocorticoid molecules in its general circulation feed back negatively on the CRH and ACTH cells of the HPA axis. Thus the glucocorticoids themselves modulate the stress response. With decreased ACTH in the circulation, the adrenal cortex secretes decreased amounts of glucocorticoids, and concentrations in the blood return to basal levels. HPA axis modulates the immune system Although glucocorticoids modulate the stress response by negative feedback on the hypothalamic CRH cells, they also regulate functions of the immune system (Figure 16.14). The immune system works to prevent the invasion of foreign pathogens and to search out and destroy those that sneak through natural barriers. It neutralizes toxins and disposes of dead, damaged, and abnormal cells. During the early phases of the stress response, the catecholamines and glucocorticoids (still at low concentrations) stimulate the immune system. 17 Stimulating the immune system ensures that a wounded animal barely escaping a predator, for example, doesn’t succumb to bacterial infection from the wound. The immune response often causes inflammation in response to infection or a wound. At higher concentrations (in later stages of the stress response and during recovery), glucocorticoids have anti-inflammatory effects and thus keep the immune system from overreacting and damaging healthy cells and tissues. Researchers now know that a web of chemical pathways allows communication among the nervous, endocrine, and immune systems. These three systems interact continuously to maintain homeostasis as an animal navigates its daily life. The inverted U Hormonal Modulation Synergism: one hormone enhances target gland’s response to another hormone (ADH, CRH & ACTH- secreting cells) Permissiveness: one hormone is required for another hormone to exert an effect (cortisol, epinephrine and blood vessels) Antagonism: one hormone opposes the action of another (Glucagon and insulin) Endocrine Control of Nutrient Metabolism Animals don’t eat continuously, and may eat meals with nutrients in proportions different from that needed by the body Cells require a continuous supply of nutrients, and the management of nutrients is under endocrine control: Storage, Mobilization and Interconversion Insulin and glucagon are produced by beta and alpha cells of islets of Langerhans in the pancreas. Nutrients come in the forms of carbohydrates, lipids and proteins. Insulin and Carbohydrates 18 Digestion -> increases in glucose and amino acids in blood -> digestive enzymes -> parasymphatetic activity -> stimulate pancreatic beta cells to release of insulin -> causes tissues, especially muscle and fat, to take up and store fatty acids, amino acids and carbohydrates. Insulin has a hypoglycemic effect, by lowering blood glucose. Promoting the synthesis of glycogen, triglycerides and proteins. Type I: not enough insulin is produced -> high blood sugar -> damages tissues/ overwhelms kidney so that sugar is excreted in urine. Type II: either not enough insulin or the tissues are insulin resistant so blood sugar is high. Risk factors include weight and sedentary lifestyle. Figure 16.15a shows the average rise and decline in plasma levels of insulin for several people after a high-carbohydrate meal. With increased glucose in the blood, insulin secretion increases; as blood glucose levels decline, so do blood levels of insulin. The spike in blood glucose following the meal shows that blood nutrient concentrations are not completely stable. However, concentrations remain far more stable than they would without the negative feedback mediated by insulin. No other hormone in the body can lower blood glucose levels. This point is made dramatically clear by people with diabetes mellitus, who secrete abnormally low amounts of insulin or who have diminished tis- sue responsiveness to insulin. After a high-carbohydrate meal, individuals with untreated diabetes experience far higher blood glucose concentrations than those without diabetes. In fact, the blood glucose levels of diabetics become so high that their kidneys are unable to recover all the glucose filtered from the blood in the process of urine formation and glucose is excreted in their urine and wasted. Chronic high levels of glucose cause damage to the eyes, kidneys, blood vessels, and nervous system. 19 Given its importance, it is not surprising that insulin secretion and the sensitivity of the body’s cells to it are influenced by several other hormones over the long term. For example, adiponectin (secreted by adipose tissue) increases cell sensitivity to insulin, and osteocalcin (secreted by osteoblast cells of bone) both promotes insulin secretion and increases cell sensitivity to it. Glucagon stabilizes blood glucose in unfed states. Glucagon is released by pancreatic alpha cells in response to: Low blood sugar. Sympathetic stimulation (stress/exercise). High levels of amino acids (high protein meal). Glucagon is secreted when blood levels of glucose and fatty acids are low, a condition typical of the unfed state. However, the rate of glucagon secretion is not increased by low levels of amino acids. Instead, glucagon secretion increases when blood levels of amino acids are high. Therefore, although glucagon is the dominant hormone during the unfed state, it is often secreted during the fed state, depending on the nutrient composition of a meal. When a high-carbohydrate meal is consumed by healthy human subjects, blood levels of glucose rise, insulin secretion increases, and glucagon secretion decreases (see Figure 16.15a). Under these conditions, the low levels of glucagon reinforce the actions of insulin. After a high-protein meal, however, both insulin and glucagon rise (Figure 16.15b). The rise in insulin promotes the incorporation of absorbed amino acids into body proteins. The rise in glucagon under these circumstances has an adaptive advantage because a high-protein meal in itself supplies little glucose, yet the brain’s preferred energy source is glucose. Increased 20 glucagon ensures an output of glucose from liver glycogen stores even in the face of high insulin levels. The interactions between insulin and glucagon in managing the appropriate use and storage of foodstuffs are key to maintaining nutrient homeostasis. We have seen that absorbed nutrients, gastrointestinal hormones, and sympathetic and parasympathetic inputs act at the and cells of the islets of Langerhans to influence secretion of glucagon and insulin. As a final consideration, we need to remember that the brain (especially the hypothalamus) continually integrates afferent information provided by secreted hormones and nutrients themselves. The brain receives information about short- term energy availability from the presence of nutrients such as glucose and free fatty acids in the blood. It receives information about long-term energy stores from the presence of circulating hormones such as leptin, which is secreted by adipose cells. Brain neural activity transduces these inputs into efferent signals that coordinate glucose production by the liver, insulin and glucagon secretion in the pancreas, and glucose uptake by muscle cells. Ongoing research continues to clarify and enhance our understanding of the broad, integrative framework involved in regulating body fat stores and blood glucose levels. These research efforts may reveal possibilities for treatment of obesity and diabetes, two major public-health concerns. Endocrine Control of Salt and Water Balance in Vertebrates Arginine vasopressin (AVP) conserves water by stimulating nephrons to take up water by increasing membrane aquaporins In absence of AVP, water cannot exit collecting duct-excreted in urine. Vasopressin—also called antidiuretic hormone (ADH)—which is a nonapeptide 21 produced by neuroendocrine cell bodies in the hypothalamus and released from their axon terminals in the posterior pituitary gland. This hormone acts to conserve water by preventing the production of a large volume of urine. All major classes of vertebrates produce hormones with antidiuretic action. Most mammals use arginine vasopressin (AVP), but some pigs and their relatives use lysine vasopressin (LVP), and nonmammalian vertebrates use the closely related arginine vasotocin (AVT). In all vertebrates, the target tissue of these hormones is the nephron of the kidney. Antidiuretic hormones stimulate the reabsorption of water from the lumen of the nephron. This means that instead of being excreted in the urine, water is returned to the extracellular fluid. The action of AVP has been studied extensively in mammals. Its effect is to stimulate the incorporation of specific aquaporin (AQP, water channel) molecules into the nephron (Figure 16.16). Different types of aquaporins exist permanently in various regions of the nephron. However, AQP-2 molecules are present in the apical membranes (those facing the lumen) of the cells of the collecting duct only when vasopressin is present. The epithelial cells of the tubules of the nephron are connected by tight junctions, which prevent movement of substances, including water, between cells. Thus water in the lumen of the tubule is destined for excretion unless it can pass through the epithelial cells back into the interstitial fluid and plasma. Receptor molecules for AVP are located on the basal side of the cells. When AVP is secreted from the posterior pituitary, it travels in the general blood circulation to the kidneys and binds to these receptors. Through second-messenger systems, AVP stimulates the movement of AQP-2 molecules from intracellular storage vesicles to the apical membrane facing the lumen. Experiments show that when exposed to AVP, the epithelial cells begin to increase their permeability to water within 1 min, and reach peak permeability in about 40 min. Water moves out of the lumen osmotically. It passes into the epithelial cell and out the basal end of the cell through a different type of AQP channel (aquaporin-3) that is always present and open. When the extracellular fluid has a high osmotic concentration or the extracellular fluid volume is low,neurons in the CNS stimulate the AVP neuroendocrinecells in the hypothalamus to secrete AVP. In the presenceof AVP, AQP-2 channels are incorporated into the apical membranes of the epithelial cells, allowing reabsorption of water. When the extracellular fluid has a low osmotic concentration or the extracellular fluid volume is large, the AVP neuroendocrine cells do not secrete AVP. In the absence of AVP, the AQP-2 channels are taken back into the cells’ cytoplasm, and none (or very few) are present in the apical membranes. Therefore, water is not reabsorbed—no matter what the osmotic gradient. The water is excreted because it cannot escape the lumen. 22 A monogamous mammal The peptides arginine vasopressin (AVP) cerebral ventricles of the brain of an unmated and oxytocin serve as hormones when released into the blood from the posterior pituitary gland. These same peptides serve as neurotransmitters when released by neurons in the CNS. Although many of the functionsof AVP and oxytocin in the CNS are not yet understood, elegant studies of two different species of rodents, the prairie vole (Microtus ochrogaster) and the montane vole (Microtus montanus), have shown that these two peptides participate in the control of behaviors related to monogamy and social attachment. The prairie vole is one of very few species of mammals that are monogamous. These animals form pair bonds in the process of mating. Over a 24-h period, a pair will engage in 15 to 30 bouts of copulation, after which they undergo a transition in behavior. They show preference for each other’s company, the male develops aggressive behaviors toward other males (which he did not show before mating), and both parents care for their young even several weeks after weaning. By contrast, montane voles do not form pair bonds after mating, they breed promiscuously, and the males do not help care for the young; in fact, even the females abandon their young 2 or 3 weeks after birth. These predictable behaviors can be demonstrated in the laboratory, and investigators have studied them using a variety of behavioral, physiological, and anatomical experimental paradigms. Groundbreaking experiments showed that if oxytocin (but not AVP) is injected into the female prairie vole, she will form a pair bond with a male without mating at all. 23 Conversely, if an antagonist to oxytocin is administered by injection into the cerebral ventricles of a female before mating, she will not form a pair bond with the male, even though mating went ahead normally. Interestingly, oxytocin does not affect males in the same way. Instead, injection of AVP into the cerebral ventricles of an unmated male prairie vole elicits mate preference and aggressive behavior toward other males. The development of these behaviors is blocked if an antagonist to AVP is injected into the male prairie vole prior to mating. In further experiments, researchers used labeling techniques to identify the distributions of postsynaptic receptors for oxytocin and AVP in the brains of the two types of voles. The monogamous prairie voles showed high densities of oxytocin receptors in the nucleus accumbens and high densities of AVP receptors in the ventral pallidum. The promiscuous montane voles did not show receptors in either of these areas, although they showed labeled receptors for AVP and oxytocin in other regions of the brain. The nucleus accumbens and the ventral pallidum are parts of the brain’s reward circuitry, which is associated with reinforcement and conditioning (the same parts of the brain thought to be involved in cocaine or nicotine addiction). A current hypothesis to explain why prairie voles are monogamous is that mating stimulates the release of oxytocin and vasopressin. These peptides, in turn, activate the reward circuits, which reinforce the formation of pair bonds. Montane voles lack receptors for oxytocin and AVP in these brain areas, so they receive no reinforcement for pair-bond formation. Ongoing studies of these two species of voles are aimed at developing a broad understanding of the neurobiological and genetic factors that underlie social bond formation in other animals, including humans. Chemical Signals at a distance Based on the distances involved, mechanisms of communication between cells can be broadly grouped into six main categories (Figure 16.19): 1. Gap junctions are formed by connexon protein channels between adjacent cells. When these channels are open, they allow ions and other small molecules to diffuse directly from one cell to the next. 24 2. Cell adhesion molecules (CAMs) on the external surface of cell membranes play important roles in signaling between adjacent cells involved in embryonic development, wound repair, and cellular growth and differentiation. 3. Neurotransmitters are released by presynaptic neurons in response to electrical signals. They diffuse across a narrow synaptic gap to interact with receptor molecules on a postsynaptic cell, which may be a neuron, muscle cell, or endocrine cell. 4. Paracrines and autocrines diffuse relatively short distances to influence cells in the local environment—including themselves, in the case of autocrines. 5. Hormones and neurohormones are specialized for long- distance communication within the animal. (From our study of the stress response, we know that cytokines also communicate across long distances; however, they function locally as well.) 6. Finally, some chemical signals act outside the animal. For example, animals of the same species communicate with pheromones, whereas animals detect kairomones to obtain chemical information about members of a different species. Chemical signals that act outside the body on members of the same or different species are also called ectocrines. Having previously considered most of these classes of intercellular communication, we will now briefly turn our attention to the local chemical messengers—paracrines and autocrines—and the external chemical messengers— pheromones and kairomones. Paracrine Paracrines diffuse a short distance to influence cells locally. Example of paracrine factor: neuromodulators diffuse from cell, influence not just postsynaptic cell, but all local cells. Newts rapidly disengage from amplexus in the face of stressor with the help of a neuromodulator, an endocannabinoid. Stressor induces corticosterone secretion -> Corticosterone binds to membrane receptors of target cells that produce an endocannabinoid -> Endocannabinoid inhibits release of excitatory NTs, reduces probability of AP in neurons that control clasping behavior. Pheromones Pheromones are chemical signals that act between individuals of the same species. Ants have many exocrine glands that produce pheromones for diverse purposes They are produced within the animal and then released into the environment. In many animals, they convey information that signals social status (for example, sex or dominance), sexual readiness, food trails, and alarm, and they elicit behaviors that are typically stereotyped and not modified by experience. Pursuing a potential mate, mating behavior, and aggressive behavior to protect a territory are often set in motion by pheromones. Physiological functions, such as the onset of puberty and estrous cycling, are also 25 influenced by pheromones. Insect Metamorphosis There are two main types of metamorphosis. In- sects such as bugs, grasshoppers, and cockroaches go through gradual metamorphosis and are referred to as hemimetabolous (hemi, “partial or gradual”; metabolous, “change”). In hemimetabolous insects, the immature (juvenile) forms, called nymphs, resemble the adult, except that they are smaller and have only immature wings and genital structures. Animals such as flies, beetles, butterflies, and moths go through dramatic metamorphosis and are referred to as holometabolous (holo, “complete”). In holometabolous insects, the larva becomes a pupa and then metamorphoses into an adult. The larva and pupa look completely different from the adult. In hemimetabolous development, the egg hatches into a nymph, which goes through several molts, or ecdyses (see Figure 16.20a). With each molt, epidermal cells underlying the cuticle (exoskeleton) synthesize a new cuticle, the old cuticle is shed (a process called ecdysis), and the new cuticle is expanded while it is still soft and pliable. To expand it, the animal takes air into the foregut and “puffs itself up.” The swallowed air applies pressure on the hemolymph (blood) and forces it into narrow lanes. The increased pressure inside the body helps fill out or unfurl external structures. Once expanded, the new cuticle hardens. The larger cuticle provides room for internal structures to grow before the next molt. The periods between molts are called instars. Hemimetabolous nymphs go through four to eight instars; each species has a characteristic number. The last nymphal instar undergoes metamorphosis into the adult. Adults have complete wings and are sexually mature. Adults do not grow or undergo additional molts. In holometabolous development, the egg hatches into a larva (see Figure 16.20b). 26 Depending on the species, larvae are referred to as grubs, caterpillars, or maggots. Like hemimetabolous nymphs, holometabolous larvae go through several molts and expand the new cuticle. With each molt, the animal increases in size. The larvae of holometabolous insects are the forms that usually cause crop damage. After several molts, holometabolous larvae enter a stage called the pupa, in which most of the larval tissues are destroyed and replaced by adult tissues. The pupa has a much thicker cuticle than the larva or adult. The pupa then metamorphoses into an adult. Adults are specialized for reproduction. In some species, such as the silkworm moth, the adult may not even feed. The holometabolous life cycle of the domesticated silkworm moth Bombyx mori. Insect Hormones Prothoracicotropic hormone (PTTH): hemolymph stimulates prothoracic gland to produce ecdysone activated ecdysone stimulates epidermis which creates new cuticle. Juvenile hormone: if present, ecdysis results in larger instar. If absent, ecdysis results in pupa or adult. In insects, the steroid hrmone ecdysone controls developmental transitions. In insects, some cells have endoreplicated DNA resulting in HUGE chromosomes shown to the left below. 27 Dark bands are part of the chromosome where the transition is represented Light puffs are parts of the chromosome where transcription is active Ecdysone levels effect genes expressed. 1 Reproduction Chapter 17 Types of Reproduction There are many types of reproduction in the animal kingdom: Asexual budding in corals and Parthenogenesis. Our focus is on sexual reproduction and what happens is that you get the formation of zygotes that then go on and form the animal and in so doing you have recombination and you have the creation of very different offspring genetically from their parents. Much more so than if the offspring would have been clonally reproduced. Why Sex Fitness/genetic variation/ natural selection In changing environments, genetic diversity that sex allows can be critical in the change of the environment. Nearly every eukaryote on the planet has the capacity to reproduce sexually and scientists still don’t know why. Sex is extremely costly and many of the proposed benefits do not seem to outweigh those costs. The costs: investments of time and energy to find and woo a mate. Sacrifice of half of the genetic contribution to the next generation, as compared with asexual cloning Reshuffling of genetic material can break apart favorable gene combinations. Possible benefits: In a changing environment, the genetic diversity that sex bestows upon a lineage can be critical for adaptation (Weismann’s hypothesis) Sexual recombination purges the genome of deleterious mutations, which can accumulate with devastating costs in asexual populations (Muller’s ratchet hypothesis) Sex can also generate beneficial mutations and bring together new gene combinations (the Fisher-Muller hypothesis) The genetic diversity introduced by sexual reproduction can help species escape parasitic infection (the Red Queen hypothesis) Red Queen Parasites will evolve to infect the most common snail genotypes in a population (Trematode worms) Sex allows the snails to produce offspring that are resistant to the parasites (Resistant offspring) Red Queen Asexual Bdelloid rotifer desiccates and blows away in the wind, leaving behind its parasites. Blowing in the wind: Bdelloid rotifers are the most successful animals that are completely asexual. But that doesn’t mean they can’t outwit their pathogenic enemies and introduce genetic novelty into the population. By riding themselves of all their water, for example, desiccated rotifers can escape parasites simply by be