GPCR mediated regulation of synaptic transmission

Vanderbilt University Medical Center, 442 Robinson Research Building, 23rd Ave. South @ Pierce, Nashville, TN 37232-6600, USA.
Progress in Neurobiology (Impact Factor: 9.99). 01/2012; 96(3):304-21. DOI: 10.1016/j.pneurobio.2012.01.009
Source: PubMed

ABSTRACT

Synaptic transmission is a finely regulated mechanism of neuronal communication. The release of neurotransmitter at the synapse is not only the reflection of membrane depolarization events, but rather, is the summation of interactions between ion channels, G protein coupled receptors, second messengers, and the exocytotic machinery itself which exposes the components within a synaptic vesicle to the synaptic cleft. The focus of this review is to explore the role of G protein signaling as it relates to neurotransmission, as well as to discuss the recently determined inhibitory mechanism of Gβγ dimers acting directly on the exocytotic machinery proteins to inhibit neurotransmitter release.

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Available from: Heidi E Hamm
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    • "GPCRs activate heterotrimeric G proteins by catalyzing the exchange of GDP for GTP in Ga, leading to dissociation of Ga$GTP from Gbg. Released Ga$GTP and Gbg have independent capacities to regulate effectors such as enzymes and ion channels. Gbg released from a variety of GPCRs directly gates G-protein-activated inwardly rectifying K + (GIRK or Kir3) channels (Betke et al., 2012; Lü scher and Slesinger, 2010) and voltage-activated Ca 2+ channels (Betke et al., 2012; Tedford and Zamponi, 2006), which influences neuronal activity throughout the brain. Typical examples of such GPCRs are the GABA B receptors that are activated by GABA, the main inhibitory neurotransmitter in the CNS (Chalifoux and Carter, 2011; Gassmann and Bettler, 2012). "
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    ABSTRACT: Activation of K(+) channels by the G protein βγ subunits is an important signaling mechanism of G-protein-coupled receptors. Typically, receptor-activated K(+) currents desensitize in the sustained presence of agonists to avoid excessive effects on cellular activity. The auxiliary GABAB receptor subunit KCTD12 induces fast and pronounced desensitization of the K(+) current response. Using proteomic and electrophysiological approaches, we now show that KCTD12-induced desensitization results from a dual interaction with the G protein: constitutive binding stabilizes the heterotrimeric G protein at the receptor, whereas dynamic binding to the receptor-activated Gβγ subunits induces desensitization by uncoupling Gβγ from the effector K(+) channel. While receptor-free KCTD12 desensitizes K(+) currents activated by other GPCRs in vitro, native KCTD12 is exclusively associated with GABAB receptors. Accordingly, genetic ablation of KCTD12 specifically alters GABAB responses in the brain. Our results show that GABAB receptors are endowed with fast and reversible desensitization by harnessing KCTD12 that intercepts Gβγ signaling.
    Full-text · Article · May 2014 · Neuron
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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., 2001, 2005; Gerachshenko 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., 2001, 2005; Gerachshenko et al., 2005; Photowala et al., 2006; Delaney et al., 2007; Yoon et al., 2007, 2008; Zhao et al., 2010; Zhang et al., 2011). "
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    ABSTRACT: 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 βγ dimers regulate the core process of exocytosis by interacting with the SNARE proteins SNAP-25, syntaxin 1A, and synaptobrevin. Gβγ binding to ternary SNARE (Soluble N-ethylmaleimide-sensitive factor Attachment protein REceptors) overlaps with synaptotagmin's calcium-dependent binding, inhibiting synaptotagmin-1 binding and fusion of the synaptic vesicle. To further explore the binding sites of Gβγ on SNAP-25, peptides based on the sequence of SNAP-25 were screened for Gβγ binding. Peptides that bound Gβγ were subjected to alanine scanning mutagenesis to determine their relevance to the Gβγ-SNAP-25 interaction. Peptides from this screen were tested in protein-protein interaction assays for their ability to modulate the interaction of Gβγ with SNAP-25. A peptide from the C-terminus, residues 193-206, significantly inhibited the interaction. Additionally, Ala mutants of SNAP-25 residues from the C-terminus of SNAP-25, as well as from the amino terminal region decreased binding to Gβ(1)γ(1). When SNAP-25 with 8 residues mutated to alanine was assembled with syntaxin 1A, there was significantly reduced affinity of this mutated t-SNARE for Gβγ, but it still interacted with synaptotagmin-1 in a Ca(2+)-dependent manner and reconstituted evoked exocytosis in BoNT/E-treated neurons. However, the mutant SNAP-25 could no longer support 5-HT-mediated inhibition of exocytosis.
    Preview · Article · Sep 2012 · Molecular pharmacology
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    [Show abstract] [Hide abstract]
    ABSTRACT: Synaptic transmission is a finely regulated mechanism of neuronal communication. The release of neurotransmitter at the synapse is not only the reflection of membrane depolarization events, but rather, is the summation of interactions between ion channels, G protein coupled receptors, second messengers, and the exocytotic machinery itself which exposes the components within a synaptic vesicle to the synaptic cleft. The focus of this review is to explore the role of G protein signaling as it relates to neurotransmission, as well as to discuss the recently determined inhibitory mechanism of Gβγ dimers acting directly on the exocytotic machinery proteins to inhibit neurotransmitter release.
    Full-text · Article · Jan 2012 · Progress in Neurobiology
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