Direct G Protein Modulation of Ca<sub>v</sub>2 Calcium Channels

Tedford, Hugo W.; Zamponi, Gerald W.

doi:10.1124/pr.58.4.11

Cited by 227 publications

(212 citation statements)

References 301 publications

(345 reference statements)

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“…We showed here that PTX affects release without altering Ca 2ϩ currents. Also, the voltage dependence of GPCRmediated inhibition of the Ca 2ϩ channels is achieved because depolarization causes dissociation of G ␤ ␥ from the channels (18,43,44). However, we have shown here that the inhibition of release by G ␤ ␥ is voltage-independent.…”

Section: Discussionmentioning

confidence: 44%

“…The affinity of GPCRs was universally shown to be high when coupled to the G protein and low when uncoupled (16,17). Pertussis Toxin (PTX) uncouples the GPCRs from their G i/o (18,19), hence reducing their affinity toward their agonists, as was indeed shown for M 2 R (5). We therefore used PTX to test whether the affinity of the GPCR plays a crucial role in release control.…”

mentioning

confidence: 99%

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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: 44%

mentioning

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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“…1). Ion channels are mainly regulated by direct interaction with G␤␥ subunits (Herlitze et al, 1996;Tedford and Zamponi, 2006;Lü scher and Slesinger, 2010). All three opioid receptors can modulate pre-and postsynaptic N-, T-, and P/Q-type Ca 2ϩ channels, suppress Ca 2ϩ influx, and thereby attenuate the excitability of neurons and/or reduce neurotransmitter release.…”

Section: Opioid Receptormentioning

confidence: 99%

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

2011

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“…120,123,124,145 The role of Ca V β subunits in voltage-dependent inhibition has been controversial with several seemingly opposing data sets and interpretations that have been reviewed in depth elsewhere. 20,38,39 Briefly, one of the central questions that arose was whether or not Ca V β and Gβγ can both bind to the channel at the same time, or whether they compete for binding to the I-II linker in a mutually exclusive manner. Overlapping binding sites for the two proteins have been identified on the I-II linker, and initial observations showed that the functional effects of Gβγ generally oppose those of Ca V β.…”

Section: Why Is the Inhibition Voltage-dependent?mentioning

confidence: 99%

G protein inhibition of Ca_V2 calcium channels

Currie¹

2010

Channels

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Direct G Protein Modulation of Ca_v2 Calcium Channels

Cited by 227 publications

References 301 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

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

G protein inhibition of Ca_V2 calcium channels

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Direct G Protein Modulation of Cav2 Calcium Channels

Cited by 227 publications

References 301 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

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

G protein inhibition of CaV2 calcium channels

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Product

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About

Direct G Protein Modulation of Ca_v2 Calcium Channels

G protein inhibition of Ca_V2 calcium channels