You are on page 1of 4

cAMP- A puppet or a puppeteer

Cyclic adenosine 3',5'-monophosphate (cyclic AMP or cAMP) is an intermediate in many physiological processes. Cyclic AMP is formed from ATP by the action of the enzyme adenylyl cyclase and converted to physiologically inactive 5'AMP by the action of the enzyme phosphodiesterase. cAMP influences normal physiology to a great extent. Some examples are: 1. Metabolism Enzymes for glycogenolysis (Glycogen phosphorylase & phosphorylase kinase), lipolysis (hormone sensitive lipase), gluconeogenesis (Pyruvate carboxylase, phosphoenolpyruvate carboxykinase & Fructose 1,6-biphosphatase) are active in phosphorylated state. cAMP via protein kinases is responsible for enzyme phosphorylation. Adrenaline, thyroxine, glucagon, methylxanthines activate these enzymes by increasing cAMP. The net effect is mobilization of stored energy. Enzymes for lipogenesis (Acetyl CoA carboxylase), glycogen synthesis (Glycogen synthase), TCA cycle (Pyruvate dehydrogenase), cholesterol synthesis (HMG CoA reductase), and glycolysis (Phosphofructokinase-1 & glucokinase) are active in dephosphorylated state. Insulin activates phosphodiesterases and reduces intracellular cAMP levels. The net effect of the hormone is storage of carbohydrate, protein, and fat. Therefore, insulin is appropriately called the "hormone of abundance." In the liver, cAMP is formed in response to glucagon, which is secreted in response to falling blood glucose; muscle is insensitive to glucagon. In muscle, the signal for increased cAMP formation is the action of norepinephrine, which is secreted in response to fear or fright, when there is a need for increased glycogenolysis to permit rapid muscle activity. 2. Circulation PGI2 inhibits aggregation of platelets by increasing cAMP, which further potentiates PGI2. ADP, TXA2 and fibrinogen induce platelet aggregation. The Gi coupled P2YAC type of purinergic receptors which mediate adenylyl cyclase inhibition by ADP are blocked by some antiplatelet drugs. So, their action is also mediated by increase in cAMP. ADH (Vasopressin) acts on V2 receptors on collecting tubule to conserve water. This is mediated by cAMP. Other actions of ADH such as vasoconstriction are mediated by Phospholipase C (V1a receptors). Increased cAMP also increases renin release (1-adrenergic receptors). Vasopressor agents that contract smooth muscle act by IP3-mediated mobilization of Ca2+, whereas agents that relax smooth muscle often act by elevation of cAMP. An increase in cAMP dampens the contraction response of smooth muscle to a given elevation of sarcoplasmic Ca2+. This molecular mechanism can explain the relaxing effect of -adrenergic stimulation on smooth muscle. D1-receptor-induced smooth muscle relaxation is presumably due to cAMP accumulation in the smooth muscle of those vascular beds in which dopamine is a vasodilator (eg. Kidney).

Acetylcholine causes vasodilation indirectly by releasing nitric oxide. But if large doses of acetylcholine are administered, vasoconstriction results directly from reduced cAMP. Catecholamines exert their inotropic effect via an action on cardiac 1-adrenergic receptors and Gs, with resultant activation of adenylyl cyclase and increased intracellular cAMP. Xanthines such as caffeine and theophylline that inhibit the breakdown of cAMP are predictably positively inotropic. Large doses of exogenous glucagon exert a positively inotropic effect on the heart without producing increased myocardial excitability because they increase myocardial cAMP. Glucagon is also used as an antidote against blockers. The opposite effects are brought about by acetylcholine via M2 receptors by decreasing cAMP. Thus, it can be concluded that increased cAMP has a positive rheological effect. 3. Gastrointestinal tract Gastric acid secretion is brought about by histamine, acetylcholine & gastrin. Histamine (H2 receptors) acts by increasing cAMP, while acetylcholine (M1 receptor) & gastrin act by increasing intracellular Ca2+. Administration of muscarinic agonists, like parasympathetic nervous system stimulation, increases the secretory and motor activity of the gut. The M3 receptor is required for direct activation of smooth muscle contraction while the M2 receptor reduces cAMP formation and relaxation caused by sympathomimetic drugs. Secretin & cholecystokinin are responsible for secretion of pancreatic juice. The hydraletic effect (increase in fluid volume & electrolyte content of juice) of secretin is mediated by increased cAMP, while the ecbolic effect (increase in enzymatic content) of CCK is mediated by Phospholipase C. It should be noted that the watery diarrhea observed in cholera and VIPoma is mediated by increased cAMP. 4. Endocrine system GHRH increases cAMP, somatostatin decreases it. ACTH, FSH, LH, hCG, TSH all act by increasing cAMP. ADH (V2) acts by increasing cAMP to conserve water.ADH (V1) & oxytocin act via Phospholipase C as smooth muscle contraction is involved. PTH increases the concentration of cAMP in the osteocytes, osteoclasts, and other target cells. This cAMP in turn is probably responsible for such functions as osteoclastic secretion of enzymes and acids to cause bone reabsorption and formation of 1,25-dihydroxycholecalciferol in the kidneys. When ACTH binds to its receptor, adenylyl cyclase is activated via Gs. The resulting increase in cAMP activates protein kinase A, and the kinase phosphorylates cholesteryl ester hydrolase (CEH), increasing its activity. Consequently, more free cholesterol is formed and converted to pregnenolone, leading to corticosteroid production. Glucocorticoids block mast cell mediator release by increasing cAMP.

LH acts via cAMP to increase conversion of cholesterol to androstenedione. FSH acts via cAMP to increase aromatase activity. Stimulation of the sympathetic nerves to the pancreas inhibits insulin secretion. The inhibition is produced by released norepinephrine acting on 2-adrenergic receptors (cAMP). However, if -adrenergic receptors are blocked, stimulation of the sympathetic nerves causes increased insulin secretion mediated by 2-adrenergic receptors (cAMP). Increased cAMP also leads to glucagon secretion mediated by 2-adrenergic receptors. So, increased cAMP leads to both insulin and glucagon secretion. Glucagon further increases cAMP, increasing insulin secretion. Insulin in turn reduces cAMP, reducing glucagon secretion, which reduces its own secretion, thus providing a feedback loop. Somatostatin inhibits both glucagon and insulin secretion by reducing cAMP. 5. Addiction Mesolimbic dopamine system is the prime target of addictive drugs. This system originates in the ventral tegmental area (VTA), a tiny structure at the tip of the brainstem, which projects to the nucleus accumbens, the amygdala, and the prefrontal cortex. When drugs of abuse are administered, dopamine concentrations in the nucleus accumbens rise, inducing dopamine-responsive cells to increase production of cAMP, which activates CREB (cAMP response element binding protein). Also, chronic drug use causes sustained activation of CREB, which enhances expression of its target genes, some of which code for proteins that then dampen the reward circuitry, leading to tolerance and dependence subsequently. This explains the addiction of drugs which increase cAMP (eg. Cocaine). However, some drugs of abuse decrease cAMP, but still are quite addictive (eg. Opiates). Acute activation of -opioid receptors by morphine or other opiates activates Gi/o proteins leading to inhibition of adenylyl cyclase, resulting in reduced cAMP production, protein kinase A (PKA) activation, and activation of the transcription factor CREB. Repeated administration of these drugs evokes a homeostatic response resulting in upregulation of adenylyl cyclases, increased production of cAMP, and increased activation of PKA and CREB. Such upregulation of cAMP signaling has been identified in the locus coeruleus, periaqueductal gray, VTA, and nucleus accumbens and contributes to opiate craving and signs of opiate withdrawal. Antidepressants that block serotonin and norepinephrine uptake, but not dopamine uptake, do not cause addiction even after prolonged use. 6. Miscellaneous Bronchodilation is promoted by cAMP, hence the use of -adrenergic agonists, methylxanthines and anticholinergics in the management of asthma and COPD. Aqueous humour production by the ciliary body is physiologically activated by cAMP, hence the use of -blockers, cholinergic agonists and 2-adrenergic agonists in the management of glaucoma. Adrenomedullin and CGRP (Calcitonin gene related peptide), 2 closely related vasoactive peptides, act by increasing cAMP. Circulating adrenomedullin levels increase during intense exercise. They also increase in a number of pathologic states, including essential hypertension,

cardiac and renal failure, and septic shock. It is currently thought that the peptide functions as a physiologic antagonist of the actions of vasoconstrictors including endothelin 1 and angiotensin II. By virtue of these actions, adrenomedullin may protect against cardiovascular overload and injury. Split personalities: Muscarinic receptors for acetylcholine- The inhibitory ones (M2, M4) act by reducing cAMP, while the excitatory ones (M1,M3,M5) act via IP3, DAG system. Dopamine receptors- Inhibitory ones (D2,D3,D4) act by reducing cAMP, while excitatory ones (D1,D5) increase cAMP. Histamine receptors- H2 acts by increasing cAMP for gastric acid secretion. H1 acts via Phospholipase C for inflammatory mediator release. Mediator release is associated with calcium influx and a fall in intracellular cAMP within the mast cell. Many of the drugs that block mediator release appear to act through the cAMP mechanism (eg, catecholamines, glucocorticoids, theophylline), others block histamine release, and still others block histamine receptors. 1 adrenergic receptors act via Phospholipase C system as they cause vasoconstriction. 2 receptors are autoreceptors and so decrease cAMP. receptors act by increasing cAMP. Prostaglandins increase cAMP in platelets, thyroid, corpus luteum, fetal bone, adenohypophysis, and lung but reduce cAMP in renal tubule cells and adipose tissue. Now, after going back to the title and doing some retrospection, one would agree that cAMP is neither a puppet nor a puppeteer. It can be best described as the flexible but strong thread which the puppeteer holds to manage the puppets. -Dr. Udit Saraf

You might also like