P2 receptors, function

The development of synthetic compounds that activate P or P2 receptors has been important for elucidating how these receptors function, because some of these compounds are more potent and selective than the parent purines, and most are more stable than the short-lived endogenous compounds adenosine and ATP. 

Epinephrine is a hormone synthesized in the adrenal glands from tyrosine (see p. 352). Its release is subject to neuronal control. This emergency hormone mainly acts on the blood vessels, heart, and metabolism. It constricts the blood vessels and thereby increases blood pressure (via ai and a2 receptors) it increases cardiac function (via P2 receptors) it promotes the degradation of glycogen into glucose in the liver and muscles (via P2 receptors) and it dilates the bronchia (also via P2 receptors). 

Lechat P, Packer M, Chalon S, Cucherat M, Arab T, Boissel JP (1998) Clinical effects of P-adrenergic blockade in chronic heart failure a meta-analysis of double-blind, placebo-controlled, randomized trials. Circulation 98 1184-1191 Liggett SB (1999) Molecular and genetic basis of p2 a

receptor function. J Allergy Clin Immunol 104 S42-S46... 

First, it provides another mechanism of desensitization, in that receptors at the cell surface produce an increase in cAMP via G whereas internalized receptors produce a decrease in cAMP levels via G,. Second, it has been found that Py subunits released from activated G, are capable of stimulating the MAPK cascade. Thus, at least for the P2 receptor, internalization functions not only to temporarily desensitize the receptor to activation of the cAMP pathway but also to initiate signaling to MAPK. Recently, a number of other G protein-coupled receptors have been found to signal to the MAPK pathway via G as well as G and G and many of these receptors seem to require internalization for such signaling to take place. 

Gachet C. Regulation of platelet functions by p2 receptors, Annu Rev Pharmacol Toxicol 2006 46 277-300,... 

Burris TP, Pelton PD, Zhou L, et al. A novel method for analysis of nuclear receptor function at natural promoters peroxisome proliferator-activated receptor y agonist actions on a P2 gene expression detected using branched DNA messenger RNA quantitation. Mol Endocrinol 1999 13 410—417. 

Metaproterenol [met a proe TER a nole], although chemically similar to isoproterenol, is not a catecholamine and is resistant to methyla-tion by COMT. It can be administered orally or by inhalation. The drug acts primarily at p2 receptors, producing little effect on the heart. Metaproterenol produces dilation of the bronchioles and improves airway function. The drug is useful as a bronchodilator in the treatment of asthma and to reverse bronchospasm (Figure 6.13). 

Therapeutic use in hypertension The cardioselective p-blockers are useful in hypertensive patients with impaired pulmonary function. Since these drugs have less effect on peripheral vascular p2 receptors, coldness of extremities, a common side effect of p-blocker therapy, is less frequent. Cardioselective p-blockers are useful in diabetic hypertensive patients who are receiving insulin or oral hypoglycemic agents. 

From the group of antagonists at ((-adrenoceptors, p,-selective blockers are mainly used (e. g., metoprolol). Owing to blockade of p2-receptors, p-blockers can impair pulmonary function, particularly in patients with chronic obstructive lung disease. 

Quick relief can be obtained with a p-adrenoceptor blocking drug (judge dose by heart rate) though these do not block all the metabolic effects of the hormone, e.g. on the myocardium, and the basal metabolic rate is unchanged. For this reason they should not be used as sole therapy except in mild thyrotoxicosis in preparation for radioiodine treatment, and should be continued in these patients until the radioiodine has taken effect. They do not alter the course of the disease, nor biochemical tests of thyroid function. Any effect on thyroid hormonal action on peripheral tissues is clinically unimportant. It is desirable to choose a drug that is nonselective for pj and p2 receptors and lacks partial agonist effect (e.g. propranolol 20-80 mg 6-8-hourly, or timolol 5 mg once daily). Usual contraindications to P-blockade (see p. 478) should be observed, especially asthma. 

Jonkers, R.E. Braat, M.C.P. Koopmans, R.P. van Boxtel, C.J. Pharmacodynamic modeling of the drug-induced down-regulation of a p2-adrenoceptor mediated response and lack of restoration of receptor function after a single high dose of prednisone. Eur. J. Clin. Pharmacol. 1995, 49 (1-2), 37-44. 

P-Adrenergic receptors ((i-ARs) are members of the superfamily of G protein-coupled receptors that are stimulated by the catecholamines epinephrine and norepinephine (1). As part of the sympathetic nervous system, P-ARs have important roles in cardiovascular, respiratory, metabolic, central nervous system, and reproductive functions. Mice lacking one or more of the three p-AR subtype genes (P, p2, and p3) have been generated to elucidate the physiological role of individual subtypes. Moreover, cells and tissues extracted from these mice have been utilized as tools to understand the molecular and cellular basis of subtype-specific receptor function. These studies are summarized in this chapter. 

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