Adenylyl cyclase Regulation

Palmer TM, Harris CA, Coote J, Stiles GL (1997) Induction of multiple effects on adenylyl cyclase regulation by chronic activation of the human A3 adenosine receptor. Mol Pharmacol 52(4) 632-640... 

Catalysis by adenylyl cyclases involves cation-mediated attack of the 3 -OH on the a-phosphate of 5 -ATP, with PPj as leaving group. It is a reversible Adenylyl Cyclases. Figure 3 Membrane localization, bireactant sequential mechanism with free cation and topology, and regulation of mammalian adenylyl cyclases. cation 5 -ATP as substrates and cAMP, cation-PP , and... 

Adenylyl Cyclases. Figure 4 Regulation of adenylyl cyclases by G-proteins. Abbreviations Hs, Hj, Rs, and Rj denote hormones and receptors that lead to stimulation or inhibition, respectively, of adenylyl cyclases, Ca and Ci are active and inactive configurations of adenylyl cyclase, Fo forskolin binding site, Gs and Gj are GTP-dependent regulatory proteins comprising their respective as, and (3y subunits. 

Hanoune J, Defer N (2001) Regulation and role of adenylyl cyclase isoforms. Annu Rev Pharmacol Toxicol 41 145-174... 

The majority of GPCRs couple to three families of G protein alpha subunits which differ in their ability to activate three distinct primary signaling cascades. The stimulatory G-protein Gas, positively regulates the activity of adenylyl cyclase causing an increase of intracellular cAMP levels as second messenger. In... 

Pituitary Adenylyl Cyclase-activating Polypeptide (PACAP) is a 38-amino acid peptide (PACAP-38), which is widely expressed in the central nervous system. PACAP is most abundant in the hypothalamus. It is also found in the gastrointestinal tract, the adrenal gland and in testis. Its central nervous system functions are ill-defined. In the periphery, PACAP has been shown to stimulate catecholamine secretion from the adrenal medulla and to regulate secretion from the pancreas. Three G-protein coupled receptors have been shown to respond to PACAP, PAQ (PACAP type I) specifically binds PACAP, VPACi and VPAC2 also bind vasoactive intestinal peptide (VDP). Activation of PACAP receptors results in a Gs-mediated activation of adenylyl cyclase. 

Clark MJ, Harrison C, Zhong H, et al Endogenous RGS protein action modulates mu-opioid signaling through Galphao effects on adenylyl cyclase, extracellular signal-regulated kinases, and intracellular calcium pathways. J Biol Chem 278 9418-9425, 2003... 

Histamine Hi, Hj Hz G, Gs Phospholipase-C to IPzto [Ca +]i regulation Stimulates adenylyl cyclase raising cAMP... 

Dopamine Di Dz, D4 D3 Gs Go, Gi G, Stimulates adenylyl cyclase raising cAMP Inhibits adenylyl cyclase, Ca +/K+ channels Phospholipase-C to IPsto [Ca +]i regulation... 

Glutamate-metabotropic mGluRl, 3, 5 mGluR2, 4, 6, 7 G, Go, Gi Phospholipase-C to IP3 to [Ca +]i regulation Inhibits adenylyl cyclase, Ca /K channels... 

Dl-iike receptors activate the Gs transduction pathway, stimulating the production of adenylyl cyclase, which increases the formation of cyclic adenosine monophosphate (cAMP) and ultimately increases the activity of cAMP-dependent protein kinase (PKA). PKA activates DARPP-32 (dopamine and cyclic adenosine 3, 5 -monophosphate-regulated phosphoprotein, 32 kDa) via phosphorylation, permitting phospho-DARPP-32 to then inhibit protein phosphatase-1 (PP-1). The downstream effect of decreased PP-1 activity is an increase in the phosphorylation states of assorted downstream effector proteins regulating neurotransmitter... 

The multiplicity of G proteins coupled to opiate receptors may explain how different opiates can bind to the same receptor yet induce different cellular responses. For example, morphine binds to the cloned rat fi receptor expressed in HEK 293, CHO and COS-7 cells and inhibits cAMP accumulation [80-82]. Morphine can be continuously applied to the cells for up to 16 h, and the potency and magnitude of morphine inhibition of adenylyl cyclase does not diminish [80, 81]. In contrast, the opiate sufentanil can bind to the same cloned fi receptor in HEK 293 cells to inhibit cAMP accumulation. However, sufentanil s actions rapidly desensitize [83]. Since both compounds bind to the same receptor, and the fi receptor is the only receptor these drugs can interact with in these cells, the ability of these two full agonists to differentially regulate the fi receptor must be due to their abilities to affect separate adaptive processes in these cells. 

Buprenorphine does not cause dependence in humans [96]. Unbke morphine, buprenorphine desensitizes the /< receptor coupling to adenylyl cyclase [80]. The desensitization occurs in the absence of any receptor internalization or downregu-lation [80]. The desensitization of the /x receptor may be the underlying basis for why buprenorphine does not cause a heightened adenylyl cyclase activity in // receptor-responsive cells. Buprenorphine s unique cellular regulation of the // receptor may explain its ability to be a non-addictive analgesic as well as its usefulness in treating opiate dependence. 

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