J. Neurosci. -- eLetters for McDavid and Currie, 26 (51) 13373-13383

QUICK SEARCH:

	Author:		Keyword(s):
Year:		Vol:		Page:

HOME | SEARCH | ARCHIVE | SUBSCRIBE | CONTACT | HELP

Electronic Letters to:

Cellular:
Sarah McDavid and Kevin P. M. Currie
G-Proteins Modulate Cumulative Inactivation of N-Type (Ca_V2.2) Calcium Channels
J. Neurosci. 2006; 26: 13373-13383 [Abstract] [Full text] [PDF]

eLetters: Submit a response to this article

Electronic letters published:

The Beta-Gamma Dimer of G-Proteins Slows Down N-type Calcium Channel Inactivation
Norbert Weiss (17 January 2007)

The Beta-Gamma Dimer of G-Proteins Slows Down N-type Calcium Channel Inactivation 17 January 2007

Norbert Weiss,
Postdoctoral Student
CNRS UMR 5123, Lab. PICM, Univ. C. Bernard Lyon1, 43 bd du 11 Nov 1918, 69622 Villeurbanne, France
Send letter to journal:
Re: The Beta-Gamma Dimer of G-Proteins Slows Down N-type Calcium Channel Inactivation

norbert.weiss{at}univ-lyon1.fr Norbert Weiss

N-type voltage-gated calcium (Ca2+) channels play a critical role in neurotransmitter release at nerve termini where they are strongly regulated by a negative feedback following activation of G-protein coupled receptors. This regulation is recognized by a set of characteristic biophysical modifications of channel activity. Hence, binding of the G- proteins Beta-Gamma dimer directly onto the channel induces a drastic current inhibition (“ON” effect), while the unbinding of the dimer following channel activation leads to a set of apparent phenotypic modifications including (i) a current deinhibition (called facilitation) at the origin of (ii) a slowing of Ca2+ current activation and inactivation kinetics, as well as (iii) a depolarizing shift of the voltage-dependence of channel activation (“OFF” effects) (Weiss et al., 2006a). “ON” effects remain difficult to characterize due to the fact that channel activation under G-protein regulation induces a current facilitation, masking the real contribution of G-proteins to channel activity. Nevertheless, it was recently described, via an indirect experimental approach, a new “ON” effect, showing that G-protein activation induces a net slowing of the voltage-dependent inactivation of N-type (Cav2.2) Ca2+ channels (Weiss and De Waard, 2006).
Here, McDavid and Currie confirm and extent on Cav2.2/Beta1b/Alpha2Delta channels this first description (McDavid and Currie, 2006). However, the observations made by the authors with the direct recording of ionic currents seem to be more difficult to interpret for two majors reasons: (i) it is not totally clear if current facilitation can occur during the 5 Hz APW stimulus. Although the authors have previously shown that no current facilitation occurs on Cav2.2/Beta2a/Alpha2Delta channels, it is known that current facilitation kinetics in the presence of the Beta1b subunit is faster than in the presence of the Beta2a subunit (Weiss et al., 2006b) suggesting that current facilitation may occur during the 5 Hz APW stimulation. Moreover, if current facilitation masks current inactivation, the reverse is also true, i.e current inactivation also masks current facilitation (Weiss et al., 2006b). Hence, absence of apparent current facilitation does not mean necessarily that the process does not take place; (ii) it is now more widely accepted that a regulated channel is a non conducting one, and in order for the channel to recuperate full activity, G-proteinsBeta- Gamma dimer need first to dissociate (Patil et al., 1996). Hence, if G- proteins reduce the functional number of Ca2+ channels (also proposed by the authors with their experiments using Omega-conotoxin GVIA), it appears difficult to understand how these channels can slow down the apparent current inactivation kinetics observed during the 5 Hz APW stimulus since these channels should not conduct Ca2+. A possible explanation could come from the concept that channel openings occur in the reluctant state, i.e channels bound to the G-proteins Beta-Gamma dimer may open with a very low opening probability (Lee and Elmslie, 2000). However, no proof can be provided that the channels still bind G-proteins during these openings.
In conclusion, it seems that direct analysis of ionic currents recorded under G-protein activation does not represent a suitable approach to study the channel inactivation under G-protein regulation. However, a very interesting finding of this study is that reducing Ca2+ entry by diminishing the total number of functional channels reduces Ca2+ dependent inactivation (CDI) of remaining channels. More extensive studies with different voltage-dependent inactivating channels (depending of the type of Beta-subunit associated) will bring interesting information on the importance of G-proteins in CDI of voltage-gated Ca2+ channels.
Lee HK, Elmslie KS (2000) Reluctant gating of single N-type calcium channels during neurotransmitter-induced inhibition in bullfrog sympathetic neurons. J Neurosci 20:3115-3128.
McDavid S, Currie KP (2006) G-proteins modulate cumulative inactivation of N-type (Ca(V)2.2) calcium channels. J Neurosci 26:13373- 13383.
Patil PG, de Leon M, Reed RR, Dubel S, Snutch TP, Yue DT (1996) Elementary events underlying voltage-dependent G-protein inhibition of N- type calcium channels. Biophys J 71:2509-2521.
Weiss N, De Waard M (2006) Introducing an alternative biophysical method to analyze direct G protein regulation of voltage-dependent calcium channels. J Neurosci Methods doi:10.1016/j.jneumeth.2006.08.010.
Weiss N, Arnoult C, Feltz A, De Waard M (2006a) Contribution of the kinetics of G protein dissociation to the characteristic modifications of N-type calcium channel activity. Neurosci Res 56:332-343.
Weiss N, Tadmouri A, Mikati M, Ronjat M, De Waard M (2006b) Importance of voltage-dependent inactivation in N-type calcium channel regulation by G-proteins. Pflugers Arch doi:10.1007/s00424-006-0184-0.