Calcium/cyclic adenosine monophosphate cAMP

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. 

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). 

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. 

Second messengers are specific intracellular components that are indirectly stimulated by the first messengers to activate intracellular components such as certain enzymes termed protein kinases (PKs). The most studied second messengers are calcium ion, inositol trisphosphate (IP3), diacylglycerol (DAG), cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP). 

The activation of the calcium second messenger system by hormones, neurotransmitters, iocal mediators, and sensory stimuii is very important in reguiating VSM contraction. Severai signai transduction mechanisms modulate intracellular calcium concentration and, therefore, the state of vascular tone. These calcium second messenger systems are the phosphatidyiinositol (PIP2)/Gq protein-coupled pathway, the cyclic adenosine monophosphate (cAMP)/Gs protein-coupied pathway, and the NO/cyclic guanosine monophosphate (cGMP) pathway. 

The H2 receptor is a 359-amino-acid protein in humans. It has some features similar to the Hi protein (e.g., N-terminal glycosylation sites) and phosphorylation sites in the C-terminal. An aspartic acid residue in the third transmembrane loop appears to be critical to agonist and antagonist binding, and threonine/aspartate and tyrosine/aspartate couples in the fifth transmembrane domain appear to be important for interaction of the imidazole part of the histamine molecule. It is positively coupled via Gas to activate adenylyl cyclase for synthesis of cyclic adenosine monophosphate (cAMP) as a second messenger. In some systems, it is coupled through Gq proteins to stimulate phospholipase C. It appears in some cells that other processes, such as breakdown of phosphoinositides, control of intracellular calcium ion levels, and phospholipase A2 activity, can be regulated by other cAMP-independent pathways. 

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