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Evolving insights regarding mechanisms for the inhibition of insulin release by norepinephrine and heterotrimeric G proteins

Norepinephrine has for many years been known to have three major effects on the pancreatic β-cell which lead to the inhibition of insulin release. These are activation of K + channels to hyperpolarize the cell and prevent the gating of voltage-dependent Ca 2+ channels that increase intracellular Ca 2+ concentration ((Ca 2+ ) i ) and trigger release; inhibition of adenylyl cyclases, thus preventing the augmentation of stimulated insulin release by cyclic AMP; and a “distal” effect that occurs downstream of increased (Ca 2+ ) i to inhibit exocytosis. All three are mediated by the pertussis toxin (PTX)-sensitive heterotrimeric Gi and Go proteins. The distal inhibitory effect on exocytosis is now known to be due to the binding of G protein βγ subunits to the synaptosomal-associated protein of 25 kDa (SNAP-25) on the soluble NSF attachment protein receptor (SNARE) complex. Recent studies have uncovered two more actions of norepinephrine on the β-cell: 1 ) retardation of the refilling of the readily releasable granule pool after it has been discharged, an action that is mediated by Gαi 1 and/or Gαi 2 ; and 2 ) inhibition of endocytosis that is mediated by Gz. Of importance also are new findings that Gαo regulates the number of docked granules in the β-cell, and that Gαo 2 maintains a tonic inhibitory influence on secretion. The latter provides another explanation as to why PTX, which blocks the effect of Gαo 2 , was initially called “islet activating protein.” Finally, there is clear evidence that overexpression of α 2A -adrenergic receptors in β-cells can cause type 2 diabetes. pancreatic β-cell K + channels adenylyl cyclases exocytosis granule pools endocytosis Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print April 4, 2012 , doi: 10.​1152/​ajpcell.​00282.​2011 Am J Physiol Cell Physiol June 15, 2012 vol. 302 no. 12 C1687-C1698 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpcell.00282.2011v1 302/12/C1687 most recent Classifications Review Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Straub, S. G. Articles by Sharp, G. W. G. PubMed PubMed citation Articles by Straub, S. G. Articles by Sharp, G. W. G. Related Content Load related web page information Current Content June 15, 2012 Alert me to new issues of Am J Physiol Cell Physiol About the Journal Calls for Papers Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0363-6143 Online ISSN: 1522-1563 var gaJsHost = (("https:" == document.location.protocol) ? "https://ssl." : "http://www."); document.write(unescape("%3Cscript src='" + gaJsHost + "google-analytics.com/ga.js' type='text/javascript'%3E%3C/script%3E")); try { var pageTracker = _gat._getTracker("UA-2924550-1"); pageTracker._trackPageview(); } catch(err) {} var gaJsHost = (("https:" == document.location.protocol) ? "https://ssl." : "http://www."); document.write(unescape("%3Cscript src='" + gaJsHost + "google-analytics.com/ga.js' type='text/javascript'%3E%3C/script%3E")); try { var pageTracker = _gat._getTracker("UA-189672-30"); pageTracker._setDomainName(".physiology.org"); pageTracker._trackPageview(); } catch(err) {} http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Cell Physiology The American Physiological Society

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