GPCR mediated regulation of synaptic transmission

Betke, Katherine M.; Wells, Christopher; Hamm, Heidi E.

doi:10.1016/j.pneurobio.2012.01.009

Cited by 133 publications

(127 citation statements)

References 251 publications

(363 reference statements)

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“…4) is suggestive of a presynaptic interaction of transducin with the synaptic machinery. Although the exact nature of this interaction remains unclear, there is considerable evidence that shows G protein-coupled receptor signaling actively regulates of synaptic transmission in the CNS (36). Both Gα t1 and Gβ 1 γ 1 translocate to the rod spherule in bright light, where they may form a heterotrimer.…”

Section: Light-evoked Transducin Translocation Enhances Signal Transmmentioning

confidence: 99%

Transducin translocation contributes to rod survival and enhances synaptic transmission from rods to rod bipolar cells

Majumder¹,

Pahlberg

Boyd³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In rod photoreceptors, several phototransduction components display light-dependent translocation between cellular compartments. Notably, the G protein transducin translocates from rod outer segments to inner segments/spherules in bright light, but the functional consequences of translocation remain unclear. We generated transgenic mice where light-induced transducin translocation is impaired. These mice exhibited slow photoreceptor degeneration, which was prevented if they were dark-reared. Physiological recordings showed that control and transgenic rods and rod bipolar cells displayed similar sensitivity in darkness. After bright light exposure, control rods were more strongly desensitized than transgenic rods. However, in rod bipolar cells, this effect was reversed; transgenic rod bipolar cells were more strongly desensitized than control. This sensitivity reversal indicates that transducin translocation in rods enhances signaling to rod bipolar cells. The enhancement could not be explained by modulation of inner segment conductances or the voltage sensitivity of the synaptic Ca 2+ current, suggesting interactions of transducin with the synaptic machinery.retina | adaptation | presynaptic modulation | SNARE complex | palmitoylation

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Section: Light-evoked Transducin Translocation Enhances Signal Transmmentioning

confidence: 99%

Transducin translocation contributes to rod survival and enhances synaptic transmission from rods to rod bipolar cells

Majumder¹,

Pahlberg

Boyd³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Presynaptic G i/o -coupled GPCRs have been shown to be relevant drug targets for anxiety and schizophrenia (Swanson et al, 2005;Patil et al, 2007), but the mechanisms for these effects are not known. The Gbg-SNARE interaction has been shown to be functionally relevant for a number of presynaptic G i/o -coupled GPCRs (Glitsch, 2006;Delaney et al, 2007;Heinke et al, 2011;Zhang et al, 2011;Betke et al, 2012). To explore these and other potential areas of therapeutic relevance further, a transgenic model deficient in the Gbg-SNARE interaction is required.…”

Section: Introductionmentioning

confidence: 99%

GβγBinds to the Extreme C Terminus of SNAP25 to Mediate the Action of G_i/o-Coupled G Protein–Coupled Receptors

et al. 2015

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G i/o -coupled G protein-coupled receptors can exert an inhibitory effect on vesicle release through several G protein-driven mechanisms, more than one of which may be concurrently present in individual presynaptic terminals. The synaptosomalassociated protein of 25 kDa (SNAP25) is a key downstream effector of Gbg subunits. It has previously been shown that proteolytic cleavage of SNAP25 by botulinum toxin A reduces the ability of Gbg to compete with the calcium sensor synaptotagmin 1 (Syt1) for binding to SNAP25 in a calcium-dependent manner. These truncated SNAP25 proteins sustain a low level of exocytosis but are unable to support serotonin-mediated inhibition of exocytosis in lamprey spinal neurons. Here, we generate a SNAP25 extreme C-terminal mutant that is deficient in its ability to bind Gbg while retaining normal calciumdependent Syt1 binding to soluble N-ethylmaleimide attachment protein receptor (SNARE) and vesicle release. The SNAP25D3 mutant, in which residue G204 is replaced by a stop codon, features a partial reduction in Gb 1 g 2 binding in vitro as well as a partial reduction in the ability of the lamprey 5-hydroxytryptamine 1b -type serotonin receptor to reduce excitatory postsynaptic current amplitudes, an effect previously shown to be mediated through the interaction of Gbg with SNAP25. Syt1 calcium-dependent binding to SNAP25D3 was reduced by a small extent compared with the wild type. We conclude that the extreme C terminus of SNAP25 is a critical region for the Gbg-SNARE interaction.

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“…Previous studies over the past 20 years have shown that the G␤␥ subunit, part of the heterotrimeric G-protein complex activated by GPCRs, has a variety of effectors that it can interact with and regulate when dissociated from G␣ upon GPCR activation (Clapham and Neer, 1997;Gautam et al, 1998;Vanderbeld and Kelly, 2000;Cabrera-Vera et al, 2003;Blackmer et al, 2005;Gerachshenko et al, 2005;Smrcka, 2008). In the presynapse, G␤␥ has been shown to be an important regulator of neurotransmission through interactions with calcium channels (Hille, 1994;Ikeda and Dunlap, 1999;Dolphin, 2003) and with the secretory machinery itself (Blackmer et al, 2001Gerachshenko et al, 2005; for review, see Betke et al, 2012). In particular, G␤␥ binds directly to the ternary SNARE complex (a trimer of SNAP-25, syntaxin 1A, and synaptobrevin), as established in biochemical as well as in vitro assays (Blackmer et al, 2001Gerachshenko et al, 2005;Photowala et al, 2006;Delaney et al, 2007;Yoon et al, 2007Yoon et al, , 2008Zhao et al, 2010;Zhang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Gβγ Inhibits Exocytosis via Interaction with Critical Residues on SolubleN-Ethylmaleimide-Sensitive Factor Attachment Protein-25

et al. 2012

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Spatial and temporal regulation of neurotransmitter release is a complex process accomplished by the exocytotic machinery working in tandem with numerous regulatory proteins. G-protein ␤␥ dimers regulate the core process of exocytosis by interacting with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins soluble N-ethylmaleimide-sensitive factor attachment protein-25 (SNAP-25), syntaxin 1A, and synaptobrevin. G␤␥ binding to ternary SNAREs overlaps with calcium-dependent binding of synaptotagmin, inhibiting synaptotagmin-1 binding and fusion of the synaptic vesicle. To further explore the binding sites of G␤␥ on SNAP-25, peptides based on the sequence of SNAP-25 were screened for G␤␥ binding. Peptides that bound G␤␥ were subjected to alanine scanning mutagenesis to determine their relevance to the G␤␥-SNAP-25 interaction. Peptides from this screen were tested in protein-protein interaction assays for their ability to modulate the interaction of G␤␥ with SNAP-25. A peptide from the C terminus, residues 193 to 206, significantly inhibited the interaction. In addition, Ala mutants of SNAP-25 residues from the C terminus of SNAP-25, as well as from the amino-terminal region decreased binding to G␤ 1 ␥ 1 . When SNAP-25 with eight residues mutated to alanine was assembled with syntaxin 1A, there was significantly reduced affinity of this mutated t-SNARE for G␤␥, but it still interacted with synaptotagmin-1 in a Ca 2ϩ -dependent manner and reconstituted evoked exocytosis in botulinum neurotoxin E-treated neurons. However, the mutant SNAP-25 could no longer support 5-hydroxytryptamine-mediated inhibition of exocytosis.

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GPCR mediated regulation of synaptic transmission

Cited by 133 publications

References 251 publications

Transducin translocation contributes to rod survival and enhances synaptic transmission from rods to rod bipolar cells

Transducin translocation contributes to rod survival and enhances synaptic transmission from rods to rod bipolar cells

GβγBinds to the Extreme C Terminus of SNAP25 to Mediate the Action of G_i/o-Coupled G Protein–Coupled Receptors

Gβγ Inhibits Exocytosis via Interaction with Critical Residues on SolubleN-Ethylmaleimide-Sensitive Factor Attachment Protein-25

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GPCR mediated regulation of synaptic transmission

Cited by 133 publications

References 251 publications

Transducin translocation contributes to rod survival and enhances synaptic transmission from rods to rod bipolar cells

Transducin translocation contributes to rod survival and enhances synaptic transmission from rods to rod bipolar cells

GβγBinds to the Extreme C Terminus of SNAP25 to Mediate the Action of Gi/o-Coupled G Protein–Coupled Receptors

Gβγ Inhibits Exocytosis via Interaction with Critical Residues on SolubleN-Ethylmaleimide-Sensitive Factor Attachment Protein-25

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GβγBinds to the Extreme C Terminus of SNAP25 to Mediate the Action of G_i/o-Coupled G Protein–Coupled Receptors