Adenylate cyclase adrenergic receptors

Strasser, R.H., Benovic, J.L., Caron, M.G. and Lefkowitz, R.J. (1986). )9-agonist- and prostaglandin Ej-induced translocation of the )5-adrenergic receptor kinase Evidence that the kinase may act on multiple adenylate cyclase-coupled receptors. Proc. Natl. Acad. Sci. USA, 83, 6362-6366... 

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...

This transmembrane signaling system involves a complex consisting of several functional proteins (Figure 7) stimulatory (e.g. P-adrenergic, dopamine Dp serotonin, vasopressin) [124] and inhibitory (e.g. a2-adrenergic, dopamine D2, opiod, and muscarinic) [125] receptors, stimulatory (Gs) and inhibitory (G ) G-proteins, and the catalytic protein, adenylate cyclase. On stimulation of a receptor, an associated G-protein binds GTP and the resulting receptor/G-protein/GTP complex then activates, or inhibits, adenylate cyclase in the catalysis of the synthesis... 

The short-acting / -agonists (Table 80-1) are the most effective broncho-dilators available. /J2-Adrenergic receptor stimulation activates adenyl cyclase, which produces an increase in intracellular cyclic adenosine monophosphate. This results in smooth muscle relaxation, mast cell membrane stabilization, and skeletal muscle stimulation. 

Other protein kinases may indirectly influence the activation of NF-kappap. For example, in contrast to the pro-inflammatory effects typically observed with activation of kinases, the elevation ofcAMP activates PKA and blocks transcription of iNOS mRNA [51,178, 229, 230]. Astrocytes contain a variety of NT receptors that are coupled to Gs-adenylate cyclase [231] and, either activation of P-adrenergic/dopamine receptors or employing agents that increase cAMP, such as forskolin (adenylate cyclase activator), PDE inhibitors [i.e. pentoxifylline], dibutyrl cAMP, or 8-bromo cAMP can attenuate lipopolysaccharide (LPS)/cytokine activated iNOS mRNA in microglia, astrocytes and a number of other cell types [51,176,177,178, 232-237]. In contrast, agents that suppress the intracellular concentration of cAM P such as H-89 and Rp-cAM P are pro-... 

Figure 6.1. Regulation of adenylate cyclase activity by G-proteins. Occupancy of receptors such as the /3-adrenergic receptor result in the activation (+) of adenylate cyclase via coupling through stimulatory G-proteins (Gs). Alternatively, occupancy of receptors such as the 2-adrenergic receptor inhibit (-) adenylate cyclase via coupling through inhibitory G-proteins (Gj).

Note that these structures are related to that for the amino acid tyrosine, from which they are derived. The adrenal glands, small pieces of tissue that ride on top of the kidneys, secrete these hormones. When they activate adrenergic receptors on the surface of muscle cells, adenylate cyclase is activated, increased cAMP results, and the cascade of events in muscle cells is started (figure 17.1). 

Janowsky, A., Okada, R, Manier, D.H., Applegate, C.D., Sulser, R, and Steranka, L.R. (1982) Role of serotonergic input in the regulation of the P-adrenergic receptor-coupled adenylate cyclase system. Science 218 900—901. 

A. Dovitzki (1986). P-Adrenergic receptors and their mode of coupling to adenylate cyclase. Physiol. Rev. 66 819-854. 

Lefkowitz, R.J. limbird, L.E. Mukheijee, I and Caron, M.G. The 6-adrenergic receptor and adenylate cyclase (1976) Biochem. Biophys. Acta 457, 1-55... 

Important intraspecies differences are found in the relative proportions of MAO-A or MAO-B in tissues [e.g., human brain has more MAO-B (about 70%) activity rat brain has more MAO-A]. After administration of an MAOI, intracellular levels of endogenous amines (e.g., NE) increase, but levels of amines not usually found in humans (tryptamine and phenylethylamine) also increase, followed by a compensatory decrease in amine synthesis because of feedback mechanisms. Levels of other amines or their metabolites (i.e., false transmitters) increase in storage vesicles and may displace true transmitters, while presynaptic neuronal firing rates decrease. After 3 to 6 weeks, brain serotonin may return to normal levels and NE levels may decrease. There is a compensatory decrease in the number of receptors, including b-adrenergic receptor-related functions (e.g., NE-stimulated adenyl cyclase). 

All of the effects of the catecholamines bound to (3 adrenergic receptors and of glucagon, ACTH, and many other hormones appear to be mediated by adenylate cyclase. This integral membrane protein catalyzes the formation of cAMP from ATP (Eq. 11-8, step a). The reaction, whose mechanism is considered in Chapter 12, also produces inorganic pyrophosphate. The released cAMP acts as the second messenger and diffuses rapidly throughout the cell to activate the cAMP-dependent protein kinases and thereby to stimulate phosphorylation of a selected group of proteins (Fig. 11-4). Subsequent relaxation to a low level of cytosolic cAMP is accomplished by hydrolysis of the cAMP by a phosphodiesterase (Eq. 11-8, step fr).166/167 jn thg absence of phosphodiesterase cAMP is extremely stable kinetically. However, it is thermodynamically unstable with respect to hydrolysis. 

The (3 adrenergic receptors are not coupled directly to adenylate cyclase but interact through an intermediary stimulatory protein Gs, which contains three subunits, a, P, and y.179 182 We know that the Gs protein associated with P adrenergic stimulation is only one of a very large number of related G proteins, so named because of their property of binding and hydrolyzing GTP. In its unactivated state the a subunit of a G heterotrimer carries a molecule of bound GDP. Apparently, the Gs proteins and the hormone receptors,... 

Stadel JM, Nambi P, Shorr RG, Sawyer DF, Caron MG, Lefkowitz RJ (1983) Catecholamine-induced desensitization of turkey erythrocyte adenylate cyclase is associated with phosphorylation of the beta-adrenergic receptor. Proc Natl Acad Sd USA 80( 11 ) 3173—3177... 

Cassel, D., and Selinger, Z. (1978). Mechanism of adenylate cyclase activation through the /1-adrenergic receptor Catecholamine-induced displacement of bound GDP by GTP. Proc. Natl. Acad. Sci. USA 75, 4155—4159. 

De Lean, A., Stadel, J. M., and Lefkowitz, R. J. (1980). A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor./. Biol. Chem. 255, 7108-7117. 

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