G protein βγ-subunits activated by serotonin mediate presynaptic inhibition by regulating vesicle fusion properties

Abstract

Neurotransmitters are thought to be released as quanta, where synaptic vesicles deliver packets of neurotransmitter to the synaptic cleft by fusion with the plasma membrane. However, synaptic vesicles may undergo incomplete fusion. We provide evidence that G protein-coupled receptors inhibit release by causing such incomplete fusion. 5-hydroxytryptamine (

Prostaglandin E1 inhibits endocytosis in the β-cell endocytosis

“…In this work it has been shown that inhibition of exocytosis by PGE 1 is abolished by a high level of Ca 2+ influx in accord with previous reports that increased Ca 2+ overcomes both serotonininduced inhibition of neurotransmitter release , Gerachshenko et al 2005, Photowala et al 2006 and NE-induced inhibition of insulin release (Zhao et al 2010b). The inhibition of release by serotonin and NE is mediated by heterotrimeric G-protein βγ subunits that block the binding of synaptotagmin to SNAP25 and thereby block SNARE protein function and exocytosis.…”

“…This distal inhibition of exocytosis in β-cells is similar to that in the central nervous system where serotonin inhibits neurotransmitter release downstream of increased [Ca 2+ ] i (Blackmer et al 2001) and in pituitary lactotrophs where endothelin blocks prolactin release; also downstream of elevated [Ca 2+ ] i (Andric et al 2005). The mechanism involves G βγ blockade of syntaxin binding to SNAP25 , Gerachshenko et al 2005, Photowala et al 2006. Although it was once believed that all physiological inhibitory effects on the β-cells were mediated by the Pertussis toxinsensitive (PTX)-sensitive heterotrimeric G i and G o proteins (Komatsu et al 1995), it has been reported that inhibition of adenylyl cyclase by PGE 1 is mediated via G z (Kimple et al 2005(Kimple et al , 2008.…”

“…The inhibition of release by serotonin and NE is mediated by heterotrimeric G-protein βγ subunits that block the binding of synaptotagmin to SNAP25 and thereby block SNARE protein function and exocytosis. Increased Ca 2+ influx overcomes the inhibition of exocytosis by an enhancement of the Ca 2+ -dependent synaptotagmin binding to SNAP25, thus preventing βγ from binding and/or displacing it and allowing exocytosis to proceed , Gerachshenko et al 2005, Photowala et al 2006.…”

“…The classification of the endocytotic mechanisms includes conventional endocytosis involving recruitment of clathrin and a group of adaptor proteins; rapid endocytosis, for example, by 'kiss and run'; bulk endocytosis (Ales et al 1999, Jahn et al 2003, Harata et al 2006, Rizzoli & Jahn 2007, Cheung et al 2010; and excess endocytosis (Eliasson et al 1996, Smith & Neher 1997. Endocytosis is Ca 2+ -dependent as has been shown in synaptic systems and neuroendocrine cells (Eliasson et al 1996, Photowala et al 2006, Rizzoli & Jahn 2007, Cheung et al 2010, including β-cells (Jarousse & Kelly 2001, Murthy & De Camilli 2003, MacDonald et al 2005, He et al 2008). …”

Cannabinoids and Epilepsy

“…CB 1 Rs are G protein-coupled receptors linked to pertussis-sensitive Gi/o α subunits. Activation of the α subunit triggers dissociation of the βγ complex, which reduces adenylate cyclase production of cyclic adenosine monophosphate [48], inhibits N-and P/Qtype voltage-gated calcium channels [31,[49][50][51][52], stimulates Atype potassium channels [53][54][55][56], activates G protein-coupled inwardly-rectifying potassium channels [57][58][59], and inhibits the vesicular release machinery [60]. These multiple mechanisms reduce presynaptic cell excitability and Ca 2+ , strongly diminishing presynaptic neurotransmitter release.…”