Gβγ acts at the C terminus of SNAP-25 to mediate presynaptic inhibition

Gerachshenko, Tatyana; Blackmer, Trillium; Yoon, Eun Ja; Bartleson, Cheryl; Hamm, Heidi E.; Alford, Simon

doi:10.1038/nn1439

Cited by 168 publications

(221 citation statements)

References 49 publications

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“…Because of the rapidity of release (a few milliseconds), it is unlikely that second messengers are involved in control of the tonic block. Rapid control could potentially be achieved (i) by GPCRs targeting Ca 2ϩ channels (31,34,41), (ii) by GPCRs targeting the release machinery via G ␤ ␥ (11,12,42), or (iii) by a rapid voltagedependent shift of the GPCR affinity and a direct interaction of the GPCR itself with the release machinery (14,15).…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms that control initiation and termination of physiological depolarization-evoked transmitter release

Kupchik

Rashkovan

Ohana

et al. 2008

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

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Ca 2؉ is essential for physiological depolarization-evoked synchronous neurotransmitter release. But, whether Ca 2؉ influx or another factor controls release initiation is still under debate. The time course of ACh release is controlled by a presynaptic inhibitory G protein-coupled autoreceptor (GPCR), whose agonist-binding affinity is voltage-sensitive. However, the relevance of this property for release control is not known. To resolve this question, we used pertussis toxin (PTX), which uncouples GPCR from its Gi/o and in turn reduces the affinity of GPCR toward its agonist. We show that PTX enhances ACh and glutamate release (in mice and crayfish, respectively) and, most importantly, alters the time course of release without affecting Ca 2؉ currents. These effects are not mediated by G␤␥ because its microinjection into the presynaptic terminal did not alter the time course of release. Also, PTX reduces the association of the GPCR with the exocytotic machinery, and this association is restored by the addition of agonist. We offer the following mechanism for control of initiation and termination of physiological depolarization-evoked transmitter release. At rest, release is under tonic block achieved by the transmitter-bound high-affinity presynaptic GPCR interacting with the exocytotic machinery. Upon depolarization, the GPCR uncouples from its G protein and consequently shifts to a low-affinity state toward the transmitter. The transmitter dissociates, the unbound GPCR detaches from the exocytotic machinery, and the tonic block is alleviated. The free machinery, together with Ca 2؉ that had already entered, initiates release. Release terminates when the reverse occurs upon repolarization.G protein-coupled receptor ͉ neurotransmitter release ͉ pertussis toxin ͉ presynaptic receptors C a 2ϩ influx is essential for physiological depolarizationinduced neurotransmitter (NT) release (1, 2). A broader, Ca 2ϩ voltage, hypothesis suggests that two factors control release: Ca 2ϩ and G protein-coupled receptors (GPCRs), whose agonist-binding affinity is voltage-dependent (3). The mechanism suggested for this control is as follows. (i) At resting potential and rest concentration (nMs) of transmitter, the release machinery (SNARE proteins and synaptotagmin) is under tonic block imposed by the transmitter-bound high-affinity (nMs) GPCR. (ii) Depolarization shifts the GPCR to a lowaffinity state ( Ms), resulting in rapid transmitter dissociation (it should be emphasized that at this stage release of NT did not occur yet, and the concentration of NT in the synapse is still in the nM range). (iii) The unbound GPCR detaches from the release machinery to relieve the tonic block. The free-release machinery together with Ca 2ϩ , which had already entered, initiates release. (iv) Upon repolarization, release terminates because the receptor returns to its high-affinity state and the tonic block is reinstated.Much of this suggested mechanism was supported experimentally (3-8) by using mainly the cholinergic neuromuscular junction (N...

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Section: Discussionmentioning

confidence: 99%

Molecular mechanisms that control initiation and termination of physiological depolarization-evoked transmitter release

Kupchik

Rashkovan

Ohana

et al. 2008

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

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“…By targeting SNAP-25, BoNT/A may prevent the SNAREmediated translocation of receptors to plasma membrane, such as N-methy-D-aspartate receptor and transient receptor potential vanilloid 1 (TRPV1) MorenillaPalao et al, 2004;Shimizu et al, 2012). In addition, it may prevent the G protein interaction with SNARE-dependent exocytotic machinery (Gerachshenko et al, 2005).…”

Section: Additional Actions Of Bont/a Mediated By Snap-25mentioning

confidence: 99%

Botulinum toxin A, brain and pain

Matak

Lacković

2014

Progress in Neurobiology

149

114

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“…Gβγ can have many immediate effectors, including PLCβ, ACs, ion channels, kinases and components of the synaptic vesicle release machinery Cabrera-Vera et al, 2003;Stehno-Bittel et al, 1995;Sullivan, 2005;Gerachshenko et al, 2005). It has been previously demonstrated that D 2 receptors can regulate ACII activity via Gβγ mediated activation of PLCβ (Tsu and Wong, 1996).…”

Section: Blocking the Gβγ Cascade Reveals A Da-induced Gα I/o Mediatmentioning

confidence: 99%

Arthropod D2 receptors positively couple with cAMP through the Gi/o protein family

Clark

Baro

2007

Comparative Biochemistry and Physiology Part B: Biochemistry an

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The pyloric network is an important model system for understanding neuromodulation of rhythmic motor behaviors like breathing or walking. Dopamine (DA) differentially modulates neurons within the pyloric network. However, while the electrophysiological actions of DA have been well characterized, nothing is known about the signaling events that mediate its effects. We have begun a molecular characterization of DA receptors (DARs) in this invertebrate system. Here, we describe the cloning and characterization of the lobster D 2 receptor, D 2αPan . We found that when expressed in HEK cells, the D 2αPan receptor is activated by DA, but not other monoamines endogenous to the lobster nervous system. This receptor positively couples with cAMP through multiple Gi/o proteins via two discrete pathways: 1) a Gα mediated inhibition of adenylyl cyclase (AC), leading to a decrease in cAMP and 2) a Gβγ mediated activation of Phospholipase Cβ (PLCβ), leading to an increase in cAMP. Alternate splicing alters the potency and efficacy of the receptor, but does not affect monoamine specificity. Finally, we show that arthropod D 2 receptor coupling with cAMP varies with the cellular milieu.

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Gβγ acts at the C terminus of SNAP-25 to mediate presynaptic inhibition

Cited by 168 publications

References 49 publications

Molecular mechanisms that control initiation and termination of physiological depolarization-evoked transmitter release

Molecular mechanisms that control initiation and termination of physiological depolarization-evoked transmitter release

Botulinum toxin A, brain and pain

Arthropod D2 receptors positively couple with cAMP through the Gi/o protein family

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