P Adrenergic receptor functions

Regulation of neurotransmitter receptors the p-adren-ergic receptor. This receptor, of which three subtypes have been cloned, mediates many of the effects of norepinephrine and epinephrine in the brain and peripheral tissues. One of the dramatic features of P-adrenergic receptor function is its rapid desensitization in response to agonist stimulation. It is now known that one important mechanism for this desensitization is phosphorylation of the receptor both by PKA and by a receptor-associated protein kinase, PARK (also called GRK2 Fig. 23-6). 

Strader CD, Sigal IS, Dixon RA. Structural basis of p-adrenergic receptor function. FASEB J 1989 3 1825-1832. 

Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ. P-Arrestin a protein that regulates P-adrenergic receptor function. Science 1990 248 1547-1550. 

Nienaber JJ, Tachibana H, Naga Prasad S V, et al. Inhibition of receptor-localized PI3K preserves cardiac p-adrenergic receptor function and ameliorates pressure overload heart failure. J Clin Invest 2003 112 1067-1079. 

P-Adrenergic receptor 2 Amino acid variants moderately associated with receptor function and agonist induced down regulation. Some variants may predispose to some types of asthma and modulate action of p-2-adrenergic drugs. 

Another mechanism to maintain CO when contractility is low is to increase heart rate. This is achieved through sympathetic nervous system (SNS) activation and the agonist effect of norepinephrine on P-adrenergic receptors in the heart. Sympathetic activation also enhances contractility by increasing cytosolic calcium concentrations. SV is relatively fixed in HF, thus HR becomes the major determinant of CO. Although this mechanism increases CO acutely, the chronotropic and inotropic responses to sympathetic activation increase myocardial oxygen demand, worsen underlying ischemia, contribute to proarrhythmia, and further impair both systolic and diastolic function. 

Hausdorff, W. P., Caron, M. G. Lefkowitz, R. J. (1990). Turning off the signal desensitization of beta-adrenergic receptor function. EASES J. 4, 2881-9. 

The gene encoding the pj-adrenergic receptor displays a fair degree of polymorphism in the human population. Like the dopamine receptors, the p -adrenergic receptor variants are often relevant to pharmacogenetics. Constitutively active mutant (CAM) and loss-of-function (LOF) variants are in evidence. 

The interaction of the Pycomplex with G-protein coupled receptor kinases (see 5.3.4, P-adrenergic receptor kinase, PARK) appears to be of special regulatory importance. The function of the Py-complex in this system is shown in Fig. 5.9. The Py-complex binds specifically to the PARK and translocates this to the cell membrane. The translocation of PARK is necessary to switch off and modulate signal transmission via adrenaline. 

Regulation of Cardiac Function by p-Adrenergic Receptor Signalling... 

Increased sympathetic activity Baroreceptors sense a decrease in blood pressure, and trigger activation of p-adrenergic receptors in the heart. This results in an increase in heart rate and a greater force of contraction of the heart muscle (Figure 16.4). In addition, vasoconstriction (ai-mediated) enhances venous return and increases cardiac preload. These compensatory responses increase the work of the heart and, therefore, can contribute to the further decline in cardiac function. 

All catecholamine receptors are metabotropic. They act by initiating metabohc processes affecting cellular functions. P-adrenergic receptors, receptors for epinephrine, and norepinephrine act by stimulatory G proteins to increase cAMP in the post-synaptic cell. cAMP binds to and activates protein-kinase enzyme. 

Rasenick, M. M., Watanabe, M., Lazarevic, M. B., Hatta, S., Hamm, H. E. Synthetic peptides as probes for G-protein function - Carboxyl terminal Gas peptides mimic Gs and evoke high-affinity agonist binding to p-adrenergic receptors. J. Biol. Chem., 1994, 269, 21519-21525. 

Larsson K, Martinsson A, Hjemdahl P. Influence of beta-adrenergic receptor function during terbutaline treatment on allergen sensitivity and bronchodilator response to terbutaline in asthmatic subjects. Chest 1992 101(4) 953-60. 

Key Words a,-Adrenergic receptor a2-adrenergic receptor P-adrenergic receptor classification function history molecular cloning pharmacology radioligand binding structure. 

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