G protein py subunits

Clapham, D. E. and Neer, E., G-protein Py subunits, Anna. Rev. Pharmacol. Toxicol., 37, 167-203, 1997. Gudermann, T., Kalkbrenner, F., and Schultz, G., Diversity and selectivity of receptor-G-protein interaction, Annu. Rev. Pharmacol. Toxicol., 36, 429-459, 1996. 

A further consideration is that receptors which primarily activate one pathway may, on occasion, activate a second pathway (Fig. 10-10). An example is the ability of GPCRs, such as a2-adrenergic receptors or mAChRs, to activate the MAPK cascade. Activation of adenylyl cyclase-linked receptors results in the release of G protein Py subunits, which, probably via an intermediary protein tyrosine kinase (PTK-X), stimulates phosphorylation of the adaptor protein SHC [36]. This in turn recruits the Grb2-SOS complex and activates the MAPK pathway. 

Kofuji, R, Davidson, N. and Lester, H. Evidence that neuronal G-protein-gated inwardly rectifying K+ channels are activated by G protein Py subunits and function as... 

G protein Py subunits subserve numerous functions in the cell 339... 

The activity of G protein Py subunits is modulated by another protein termed phosducin [16]. Phosducin is a cytosolic protein enriched in retina and pineal gland but also expressed in brain and other tissues. Phosducin binds to G protein Py subunits with high affinity. The result is prevention of Py subunit reassociation with the a subunit. In this way, phosducin may sequester Py subunits, which initially may prolong the biological activity of the a subunit. However, eventually this sequestration may inhibit G protein activity by preventing the direct biological... 

The possibility that Ai receptors influence targets downstream of calcium entry has also been proposed because, at the amphibian neuromuscular junction, adenosine inhibited acetylcholine release by a mechanism that did not depend on calcium entry into the presynaptic terminal (Hunt et al. 1994 Robitaille et al. 1999). This downstream pathway may also involve G-protein Py subunits (Blackmer et al. 2001). 

Two main pathways lead to the modulation of neurotransmitter release by inhibitory P2Y receptors, both involving modulation of VSCC. The first pathway, mediated by Gl /() proteins, results in PTX-sensitive, voltage-dependent inhibition of VSCC by the G-protein py subunits (Delmas et al. 1999 Dolphin 2003 mechanism 1 in Figure 3). Evidence for this pathway was initially obtained in adrenal chromaffin cells, where ATP and ADP reduced Ca2+ currents through activation of receptors... 

Fig. 3 Mechanisms involved in presynaptic inhibition through P2Y receptors. P2Yi 2,4,12 receptors may couple to PTX-sensitive proteins and mediate voltage-dependent inhibition of calcium currents by direct interaction of the Py subunits with the N-type VSCC (1). The P2Yi, 2,4 receptor subtypes may also couple to PTX-insensitive Gq/n proteins and mediate voltage-independent inhibition of Ca2+ currents by (2) direct interaction of G protein Py subunits with the channel or (3) activation of phospholipase C (PLC), causing depletion of membrane phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2).

Crespo P, Xu N, SIMONDS WF, GUTKIND JS. Ras-dependent activation of MAP kinase pathw mediated by G-protein Py subunits. Nature 3 418-420,1994. 

Kim D, Lewis DL, GRAZIADEI L. G-protein py-subunits activate the cardiac muscarinic K channd via pbotpbolipase Araft(/e337 SS7-S59,1989. 

THOMASON PA, James SR, Casey PJ, Downes CP. A G-protein Py-subunit-responsive phospboinositide 3-kinase activity in human platdet cytosol. JBiol Chem 269 16525-16528,1994. 

TOUHARA K, Hawes BE, van Biesen T, LEFKOWHZ RJ. G protein Py subunits stimulate pho horylation of the She adapter protein. Proc Natl Acad Sd USA 92 9284-9287,1995. 

Zhang J, Benovic JL, SUGAI M, WETZKER R, Gout I, RTITENHOUSE SE. Sequestration of a G-protein Py subunit or ADP-ribosylation of riio can inhibit thrombin-induced activatiem of platelet phosphoinositide 3-kinases. JBiol Chem 270 6589-6594,1995. 

Both isoforms of pARK are cytosolic proteins which need to be translocated to the cell membrane in order to phosphorylate the receptors. This translocation appears to occur via three "membrane anchors" First, the kinases require the agonist-occupied, active conformation of the receptors to which they bind [13]. Second, the kinases bind to the G protein Py subunits which may, in addition to the translocation, result in activation of the kinases [14,15]. This process appears to be supported by specific combinations of py subunits much better than by others [16]. And third, recent data indicate that the kinase binds to phosphatidylinositol bisphosphate (PIP2) via a C-terminal pleckstrin homology domain [17]. At least the first two modes of membrane anchoring and activation appear to be involved in the strictly agonist-dependent action of PARK on p-adrenergic receptors. 

The complexity of the network that appears to be involved in the cross-talk between various receptors of the PLC pathway suggests the existence of multiple mechanisms to accomplish this complicated regulatory task. It is conceivable that interaction of GRKs with specific G protein Py subunits allows for differential desensitization of different receptors [16]. However, in addition to the well characterized GRK mechanism the lateral segregation model provides an appealing mechanism to explain some of the observed phenomena [5]. 

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