Adrenergic receptors receptor

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. 

There is another large class of receptors whose occupancy by an agonisf leads to inhibition of adenylate cyclase. These include the tt2 adrenergic receptors, receptors for acetylcholine, adenosine, prostaglandin E2 (Chapter 21), somatostatin, and some receptors for dopamine. Their responses are mediafed by inhibitory proteins Gj, which closely resemble Gg in their sizes, amino acid sequences, and heterotrimeric structures, but which inhibit adenylate cyclase when activated. A clear distinction between the Gg and Gj proteins is evident in the fact that Gg is irreversibly activated by the action of cholera toxin, while G loses its ability to respond to occupied receptors when modified by the action of Pertussis toxin (Box 11-A). A specialized heterotrimeric G protein known as transducin mediates the light-induced activation of a cyclic GMP phosphodiesterase in the retina " (see Chapter 23). Its a subunit is designated aj. The related gustducin is found in taste buds. ... 

Muntz KH, Zhao M, Miller JC. Downregulation of myocardial P-adrenergic receptors. Receptor subtype selectivity. Circ Res 1994 74 369-375. 

Receptor antagonists are not the drugs of choice in patients with pheochromocytoma, because a vasoconstrictor response to epinephrine can still result from activation of unblocked vascular (X2 adrenergic receptors, Receptor antagonists are attractive drugs for hypertensive patients with benign prostatic hyperplasia, since they also improve urinary symptoms. 

RNHCH.CH(OHlCH— R R P Adrenergic receptor blocking agents 473... 

RNHCH CH(OHiCH - heteroarvl H /3-Adrenergic receptor blocking agents 179... 

The ability of receptors to couple to G-proteins and initiate GTPase activity may also be independent of ligand. Thus, specific mutations in a- and P-adrenergic receptors have led to receptors that mediate agonist-independent activation of adenylyl cyclase (69,70). These mutations presumably mimic the conformational state of the ligand-activated receptor when they are activated conventionally by ligands. 

Ephedrine, which is not a catecholamine, has weak oral activity as a bronchodilator and although it has some direct action at adrenergic receptors, its predominant mode of action is by displacing norepinephrine from storage vesicules. 2"Agonists which are in use or are under investigation are the result of quests for improved selectivity, retention of potency, oral activity, and longer duration of action. 

Aerosol adniinistration of isoproterenol produces a prompt (2—5 minutes) intense bronchodilatation of relatively short (1 h) duration. The lack of P2-selectivity leads, in many cases, to tachycardia and blood pressure elevation. Also, use of isoproterenol, like all other known P-agonists, results in a down-regulation, or desensitization, of P-adrenergic receptors. This desensitization is only partial, and after time (depending on dose, patient, and agent), a stable, less responsive state is achieved in which P-agonists remain effective. Isoproterenol has been widely used for many years. 

In general, activation of alpha-1 adrenergic receptors causes a contraction of smooth muscle and of blood vessels, pilomotor muscles, dilator pupillae, vas deferens, nictitating membrane, splenic capsule, and sphincters of the intestine and urinary bladder and of the bile duct. An exception is the relaxation of the smooth muscle of the intestine. Prazosin [19216-56-9] indoramin [26844-12-2] and WB-4101 are relatively selective antagonists of these receptors. 

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

Figure 13.3 G protein-mediated activation of adenylate cyclase by hormone binding. Hormone binding on the extracellular side of a receptor such as the P adrenergic receptor activates a G protein on the cytoplasmic ATP side. The activated form of the G protein...

E. G protein-conpled receptors /3-Adrenergic receptor kinase (BARK) Rhodopsin kinase II. Ser/Thr/Tyr protein kinases MAP kinase kinase (MAPK kinase) —TEY— phosphorylation by... 

Risperidone (11) was also included among a a 1-adrenergic receptor antagonists to study a quantitative structure-activity relationship (99BMC2437). A pharmacophore model for atypical antipsychotics, including 11, was established (00MI41). An increased plasma level of 11 and 9-hydroxyrisperidone (12) was observed in combination with paroxetine (01 MI 13). The effect of vanlafaxine on the pharmacokinetics of 11 was reported (99MI13). 

Sympathetic blocking agent. A drug that binds to, but does not stimulate, adrenergic receptors of the 3-type. 

Some of the side effects due to beta blockers such as the slowing of heart rate can be counteracted by administration of drugs which antagonize the alpha adrenergic receptors. The... 

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