Gβγ Decreases Quantal Size

Science's STKE  06 Sep 2005:
Vol. 2005, Issue 300, pp. tw322
DOI: 10.1126/stke.3002005tw322

In a study of rat adrenal chromaffin cells, which have dense-core secretory granules, Chen et al. reported that release of Gβγ in response to activation of Gi/o-coupled receptors inhibited secretion by reducing quantal size. The reduction in quantal size was measured by amperometry in response to application of adenosine triphosphate (ATP), opioids, or somatostatin. Although each agonist partially inhibited calcium signaling, each also inhibited secretion induced by caffeine, which bypasses plasma membrane calcium channels to promote release of calcium directly from intracellular stores. Thus, application of ATP, for example, which can inhibit plasma membrane calcium channels, does not affect calcium transients induced by caffeine, yet still inhibits secretion. The agonists did not inhibit secretion stimulated by activation of muscarinic acetylcholine receptors (mAChR), but pharmacological inhibition of protein kinase C (PKC), which is downstream of the Gq-coupled mAChR, restored ATP-, opioid,-, and somatostatin-mediated inhibition of secretion. ATP was confirmed to act through the Gi/o-coupled receptor P2Y. Somatostatin and the opioid agonist tested also act through a Gi/o-coupled receptor; however, the effects of these agonists appeared to be mediated through the βγ and not the α subunits. The mechanism by which βγ inhibited secretion appeared not to involve the known kinases downstream of βγ, because pharmacological inhibition of phosphoinositide 3-kinase (PI3K), phospholipase β2, serine-threonine kinases, or tyrosine kinases did not affect caffeine-induced secretion. Sequestration of βγ with a membrane-permeable peptide blocked ATP-induced inhibition of caffeine-induced secretion, and whole-cell dialysis of Gβ1γ2 into the cells inhibited depolarization-induced secretion. The authors propose that Gβγ limits the open time of the fusion pore, but the exact target of βγ for this effect remains to be determined.

X.-K. Chen, L.-C. Wang, Y. Zhou, Q. Cai, M. Prakriya, L.-K. Duan, Z.-H. Sheng, C. Lingle, Z. Zhou, Activation of GPCRs modulates quantal size in chromaffin cells through Gβγ and PKC. Nat. Neurosci. 8, 1160-1168 (2005). [PubMed]