Abstract
The direct inhibition of N- and P/Q-type calcium channels by G protein betagamma subunits is considered a key mechanism for regulating presynaptic calcium levels. We have recently reported that a number of features associated with this G protein inhibition are dependent on the G protein beta subunit isoform (Arnot, M. I., Stotz, S. C., Jarvis, S. E., Zamponi, G. W. (2000) J. Physiol. (Lond.) 527, 203-212; Cooper, C. B., Arnot, M. I., Feng, Z.-P., Jarvis, S. E., Hamid, J., Zamponi, G. W. (2000) J. Biol. Chem. 275, 40777-40781). Here, we have examined the abilities of different types of ancillary calcium channel beta subunits to modulate the inhibition of alpha(1B) N-type calcium channels by the five known different Gbeta subunit subtypes. Our data reveal that the degree of inhibition by a particular Gbeta subunit is strongly dependent on the specific calcium channel beta subunit, with N-type channels containing the beta(4) subunit being less susceptible to Gbetagamma-induced inhibition. The calcium channel beta(2a) subunit uniquely slows the kinetics of recovery from G protein inhibition, in addition to mediating a dramatic enhancement of the G protein-induced kinetic slowing. For Gbeta(3)-mediated inhibition, the latter effect is reduced following site-directed mutagenesis of two palmitoylation sites in the beta(2a) N-terminal region, suggesting that the unique membrane tethering of this subunit serves to modulate G protein inhibition of N-type calcium channels. Taken together, our data suggest that the nature of the calcium channel beta subunit present is an important determinant of G protein inhibition of N-type channels, thereby providing a possible mechanism by which the cellular/subcellular expression pattern of the four calcium channel beta subunits may regulate the G protein sensitivity of N-type channels expressed at different loci throughout the brain and possibly within a neuron.
Highlights
The inhibition of presynaptic calcium channels by the activation of seven-helix transmembrane receptors is an important mechanism for modulating calcium influx into presynaptic nerve termini
We have recently reported that a number of features associated with this G protein inhibition are dependent on the G protein  subunit isoform
G␥ Modulation of N-type Channels Is Dependent on the Nature of the Calcium Channel  Subunit—Upon coexpression of N-type calcium channels with G protein ␥ subunits, the channels undergo a tonic G protein inhibition and enter a reluctant gating mode that is seen at the whole cell level as a slowed time course of current activation and a decrease in peak current amplitude [10]
Summary
The inhibition of presynaptic calcium channels by the activation of seven-helix transmembrane receptors is an important mechanism for modulating calcium influx into presynaptic nerve termini. It is widely accepted that G␥ physically interacts with the domain I–II linker [14, 15] as well as the carboxyl-terminal region of the channel [8, 16] and that both regions bind the ancillary calcium channel  subunit [17, 18]. In view of this target site overlap, it may not be surprising to note that the presence of the calcium channel  subunit has been shown to antagonize G protein action (7, 19 –21). The nature of the calcium channel  subunit is an important determinant of G protein efficacy and may give rise to substantial heterogeneity in the susceptibility of native N-type channels to G protein inhibition
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