Calcium/cyclic adenosine monophosphate

Factors controlling calcium homeostasis are calcitonin, parathyroid hormone(PTH), and a vitamin D metabolite. Calcitonin, a polypeptide of 32 amino acid residues, mol wt - SGOO, is synthesized by the thyroid gland. Release is stimulated by small increases in blood Ca " concentration. The sites of action of calcitonin are the bones and kidneys. Calcitonin increases bone calcification, thereby inhibiting resorption. In the kidney, it inhibits Ca " reabsorption and increases Ca " excretion in urine. Calcitonin operates via a cyclic adenosine monophosphate (cAMP) mechanism. 

Theophylline and aminophylline may produce bronchodilation by inhibition of phosphodiesterase (thereby increasing cyclic adenosine monophosphate levels), inhibition of calcium ion influx into smooth muscle, prostaglandin antagonism, stimulation of endogenous catecholamines, adenosine receptor antagonism, and inhibition of release of mediators from mast cells and leukocytes. 

Action on the CNS depends directly on the dose of administered drug, and can be manifested as fatigue, anxiety, tremors, and even convulsions in relatively high doses. Theophylline acts on the cardiovascular system by displaying positive ionotropic and chronotropic effects on the heart, which, can likely be linked to the elevated influx of calcium ions by modulated cyclic adenosine monophosphate and its action on specific cardiac phosphodiesterases. In the gastrointestinal system, methylxanthines simultaneously stimulate secretion of both gastric juice and digestive enzymes. 

The activation of adenylyl cyclase enables it to catalyze the conversion of adenosine triphosphate (ATP) to 3 5 -cyclic adenosine monophosphate (cAMP), which in turn can activate a number of enzymes known as kinases. Each kinase phosphorylates a specific protein or proteins. Such phosphorylation reactions are known to be involved in the opening of some calcium channels as well as in the activation of other enzymes. In this system, the receptor is in the membrane with its binding site on the outer surface. The G protein is totally within the membrane while the adenylyl cyclase is within the membrane but projects into the interior of the cell. The cAMP is generated within the cell (see Rgure 10.4). 

Autonomic receptors further regulate calcium influx through the sarcolemma (Fig. 15.1). (3-Adrenergic stimulation results in the association of a catalytic subunit of a G protein coupled to the (3-receptor. This stimulates the enzyme adenylyl cyclase to convert ATP to cyclic adenosine monophosphate (cAMP). Increasing cAMP production results in a cAMP-dependent phosphorylation of the L-type calcium channel and a subsequent increase in the probability of the open state of the channel. This translates to an increase in transsarcolemmal calcium influx during phase 2 (the plateau phase) of the cardiac muscle action potential. The effects of transient increases in intracellular levels of cAMP are tightly con-... 

Several classes of drugs, notably the antipsychotics, discussed in Chapter 34, interfere with dopaminergic transmission. In general, dopamine appears to be an inhibitory neurotransmitter. Five dopamine receptors have been identified the most important and best studied are the Dj. and D2.receptor groups. The Dj receptor, which increases cyclic adenosine monophosphate (cAMP) by activation of adenylyl cyclase, is located primarily in the region of the putamen, nucleus accum-bens, and in the olfactory tubercle. The D2 receptor decreases cAMP, blocks certain calcium channels, and opens certain potassium channels. 

Uterine relaxation is mediated in part through inhibition of MLCK. This inhibition results from the phosphorylation of MLCK that follows the stimulation of myometrial (3-adrenoceptors relaxation involves the activity of a cyclic adenosine monophosphate (cAMP) mediated protein kinase, accumulation of Ca++ in the sarcoplasmic reticulum, and a decrease in cytoplasmic Ca. Other circulating substances that favor quiescence of uterine smooth muscle include progesterone, which increases throughout pregnancy, and possibly prostacyclin. Progesterone s action probably involves hyperpolarization of the muscle cell membrane, reduction of impulse conduction in muscle cells, and increased calcium binding to the sarcoplasmic reticulum. 

Plasma calcium concentration is the principal factor regulating PTH synthesis and release. The increase in PTH synthesis and secretion induced by hypocalcemia is believed to be mediated through activation of parathyroid gland adenylyl cyclase and a subsequent increase in intracellular cyclic adenosine monophosphate (cAMP). 

Mectianism of Action A cardiac inotropic agent that inhibits phosphodiesterase, which increases cyclic adenosine monophosphate and potentiates the delivery of calcium to myocardial contractile systems. Therapeutic Effect Relaxes vascular muscle, causing vasodilation. Increases cardiac output decreases pulmonary capillary wedge pressure and vascular resistance. 

Manna s data (1991) of the efficacy of a nimodipine and lithium combination are of particular interest in reference to the above hypotheses related to combined effects on calcium-related mechanisms. Lithium obviously exerts complex effects on a variety of systems in brain, but its effects on phosphoinositide turnover and cyclic adenosine monophosphate and downstream effects on 1,4,5-inositol triphosphate (IP3) metabolism in calcium-related processes (as reviewed by Berridge 1989 H. L. Meltzer 1990 and... 

Other positive inotropes Inamrinone (generic] Milrinone (Primacor] Enhance myocardial contractility by prolonging effects of cyclic adenosine monophosphate (cAMP], which increases intracellular calcium levels and promotes stronger actin-myosin interaction in cardiac cells... 

There are three important ADP receptors on the platelet surface. The P2X, is related with the rapid influx of calcium into the cytosol the P2Y1 mediates mobilization of calcium through activation of phospholipase C and shape change, and the P2Y12 receptor is coupled to adenyl cyclase inhibition mediated by a G-protein with subsequent decrease of the cyclic adenosine monophosphate (cAMP). The decrease of cAMP stimulates dephosphorylation of vasodilator-stimulated phosphoprotein that is closely correlated with the GPIIb/llla activation. Thienopyridines compounds promote platelet inhibition mainly by blocking the P2Y12 receptor. 

Mechanism of action The methylxanthines may act by several mechanisms, including translocation of extracellular calcium, increase in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) caused by inhibition of phosphodiesterase, and blockade of adenosine receptors. 

Liu YF, Civelli O, Zhou QY, Albert PR (1992b) Cholera toxin-sensitive 3, 5 -cyclic adenosine monophosphate and calcium signals of the human dopamine-Dl receptor selective potentiation by protein kinase A. Mol Endocrinol 6 1815-1824. 

Abnormal G protein functioning dysregulates adenylate cyclase activity, phosphoinositide responses, sodiurrypotassium/calcium channel exchange, and activity of phospholipases. Abnonnal cyclic adenosine monophosphate and phosphoinositide secondary messenger system activity. 

The main effect of adrenergic stimulation is to enhance the intracellular adenylyl cyclase activity. This in turn increases cyclic adenosine monophosphate levels. Protein kinase A is activated which modulates, i.e. phosphorylates, calcium and potassium channels. Phosphorylation of the calcium channel increases the inward current leading to early after-depolarization. 

Features of lithium-induced hyperparathyroidism include a) a low urinary calcium excretion and the absence of nephrolithiasis b) normal urinary cyclic adenosine monophosphate excretion and c) normal plasma inorganic phosphate [32]. In lithium-induced hypercalcemia, a higher frequency of conduction defects has been noted [47]. Lithium also inhibits par-... 

Firstly, Cd causes renal damage with effects principally on renal tubular cells, i.e. the site of la,25-dihy-droxyvifamin D synfhesis resulfing in an infrinsic vitamin D deficiency. This will impair the gastrointestinal absorption of calcium, reduce the calcium incorporation in bone and ultimately result in the development of osteomalacia. It is well known that la,25-dihydroxyvi-tamin D is the biologically active metabolite of vitamin D. As there is a sequential relationship between the synthesis of la,25-dihydroxyvitamin D in the kidney and cyclic-adenosine monophosphate, adenylcyclase, parathyroid hormone, a direct interference of Cd with any of these steps cannot be excluded. 

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