Voltage-gated Ca2+ channel activity is modulated by a
variety of substances in many different pathways. Dunlap's
research focuses on G-protein- coupled pathways involved
in modulation of N-type Ca2+ channels. Some of these pathways
involve direct binding of G-protein subunits to calcium
channels, which induces a transient voltage-dependent inhibition
of N-type channel activity.
Other pathways involve intermediate enzymes and induce
long-lasting voltage-independent inhibition of N- type channels.
It is known that G- protein subunits act as mediators of
receptor-effector coupling and that G- (aßg
are involved in regulation of effectors. The number of different
genes encoding G-ßg had
suggested a possible selectivity of these different G-ßg
subunit types for different effectors, but no previous studies
clearly support any selectivity. Dunlap's group has recently
found evidence for such selectivity in vivo, by using recombinant
G-ßg complexes in chick
sensory neurons.
Specifically, G-ßg complexes
containing one ß subunit activate the phospholipase
Cß pathway (PLCß) inducing N-type Ca2+ current
inhibition, whereas G-ßg
complexes containing a different ß subunit have no
effect. Interestingly, this selectivity is not observed
with an in vitro enzyme assay, suggesting that intact cell
may contain modulating factors that selectively enhance
interactions between effectors and particular G-ßg
complexes.
Overall these experiments show that selective activation
of pathways inhibiting N-type Ca2+ channels by G-ßg
complexes may play an important role in neural processes
such as transmitter release.
