The PACAP receptors are G-protein coupled and PACAP-R1 is the most abundant in both central and peripheral tissues. PACAP may also modulate estrogen's role in the potentiation of the acute stress response. Evidence also points to PACAP's involvement in the autonomic response to stress through increased secretion of catecholamines. PACAP may play a role in the production of CRH and have a modulatory role in multiple levels of the HPA axis. The HPA axis is regulated by pituitary adenylate cyclase-activating polypeptide (PACAP). Cortisol's inactive form, cortisone, is catalyzed to its active form, cortisol, by 11 beta-hydroxysteroid dehydrogenases. ACTH stimulates the adrenal cortex to secrete glucocorticoid hormones, such as cortisol, into the circulation. The released CRH then stimulates the anterior pituitary gland to release adrenocorticotrophin hormone (ACTH) into the bloodstream. Serum cortisol level describes the body's total cortisol level, of which 80% is bound to cortisol binding globulin (CBG) and 10% is bound to albumin. In exposure to stress, the expression of CRH-BP increases in a time-dependent fashion, which is thought to be a negative feedback mechanism to decrease the interaction of CRH with CRH-R1. The role of CRH-BP as a controller of the bioavailability of CRH has support by studies finding 40 to 60% of CRH in the brain is bound by CRH-BP. CRH-BP gets expressed in the liver, pituitary gland, brain, and placenta. CRH-R2 is expressed primarily in peripheral tissues including skeletal muscles, gastrointestinal tract, and heart, as well as in subcortical structures of the brain. Cortisol releasing hormone binding protein CRH-BP binds with CRH with a higher affinity than CRH to its receptors. It is the key receptor for the stress-induced ACTH release from the anterior pituitary. The CRH released from the hypothalamus acts on two receptors CRH-R1 and CRH-R2.CRH-R1 is widely expressed in the brain in mammals. The slow response is due to activation of the HPA axis resulting in the release of Corticotropin-releasing hormone (CRH) from the paraventricular nucleus of the hypothalamus into the circulation. In addition, SAM activation cases behavioral activation (enhanced arousal, alertness, vigilance, cognition, focused attention, and analgesia). It also leads to reduced intestinal motility, cutaneous vasoconstriction, bronchiolar dilatation. Activation of these receptors results in, contraction of smooth and cardiac muscles cells leading to vasoconstriction, increased blood pressure, heart rate, cardiac output, skeletal muscle blood flow, increased sodium retention, increased glucose levels (due to glycogenolysis and gluconeogenesis), lipolysis, increased oxygen consumption, and thermogenesis. The norepinephrine(NE) and epinephrine(E), once released, bind to specific membrane-bound G-protein receptors to initiate an intracellular cAMP signaling pathway that rapidly activates cellular responses.
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The released E and NE interact with α- adrenergic and β-adrenergic receptors, present in the central nervous system and on the cell membrane of smooth muscles, and other organs throughout the body.
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The fast response due to activation of SAM results in increased secretion of norepinephrine(NE) and epinephrine(E) from the adrenal medulla into the circulation and increased secretion of NE from the sympathetic nerves and thus result in elevated levels of NE in the brain. The physiology of stress response has two components a slow response, mediated by the HPA axis, and a fast response, mediated by the SAM axis.
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But if the exposure to a stressor is actually or perceived as intense, repetitive (repeated acute stress), or prolonged (chronic stress), the stress response becomes maladaptive and detrimental to physiology e.g., exposure to chronic stressors can cause maladaptive reactions including depression, anxiety, cognitive impairment, and heart disease. The stress response is adaptive, to begin with, that prepares the body to handle the challenges presented by an internal or external environmental challenge (stressor) e.g., the body's physiologic responses to trauma and invasive surgery serve to attenuate further tissue damage. A stress response is mediated by a complex interplay of nervous, endocrine, and immune mechanisms that involves activation of the sympathetic-adreno-medullar (SAM) axis, the hypothalamus-pituitary-adrenal (HPA) axis, and immune system.
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The stimuli are called stressors and physiological and behavioral changes in response to exposure to stressors constitute the stress response. Any physical or psychological stimuli that disrupt homeostasis result in a stress response.