Calcium channel beta subunits differentially regulate the inhibition of N-type channels by individual G beta isoforms

The direct inhibition of N- and P/Q-type calcium channels by G protein beta gamma subunits is considered a key mechanism for regulating presynaptic ca lcium levels. We have recently reported that a number of features associate d with this G protein inhibition are dependent on the G protein beta subuni t isoform (Arnot, M. I., Stotz, S. C., Jarvis, S. E., Zamponi, G. W. (2000) J. Physiol. (Loud.) 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 ancilla ry calcium channel beta subunits to modulate the inhibition of alpha (1B) N -type calcium channels by the five known different G beta subunit subtypes. Our data reveal that the degree of inhibition by a particular G beta subun it is strongly dependent on the specific calcium channel beta subunit, with N-type channels containing the beta (4) subunit being less susceptible to G beta gamma -induced inhibition. The calcium channel beta (2a) subunit uni quely slows the kinetics of recovery from G protein inhibition, in addition to mediating a dramatic enhancement of the G protein-induced kinetic slowi ng. For G beta (3)-mediated inhibition, the latter effect is reduced follow ing site-directed mutagenesis of two palmitoylation sites in the beta (2a) N-terminal region, suggesting that the unique membrane tethering of this su bunit serves to modulate G protein inhibition of N-type calcium channels. T aken together, our data suggest that the nature of the calcium channel beta subunit present is an important determinant of G protein inhibition of N-t ype channels, thereby providing a possible mechanism by which the cellular/ subcellular expression pattern of the four calcium channel beta subunits ma y regulate the G protein sensitivity of N-type channels expressed at differ ent loci throughout the brain and possibly within a neuron.