DIRECT INTERACTION OF G-BETA-GAMMA WITH A C-TERMINAL G-BETA-GAMMA-BINDING DOMAIN OF THE CA2-PROTEIN-COUPLED RECEPTORS( CHANNEL ALPHA(1) SUBUNIT IS RESPONSIBLE FOR CHANNEL INHIBITION BY G)
N. Qin et al., DIRECT INTERACTION OF G-BETA-GAMMA WITH A C-TERMINAL G-BETA-GAMMA-BINDING DOMAIN OF THE CA2-PROTEIN-COUPLED RECEPTORS( CHANNEL ALPHA(1) SUBUNIT IS RESPONSIBLE FOR CHANNEL INHIBITION BY G), Proceedings of the National Academy of Sciences of the United Statesof America, 94(16), 1997, pp. 8866-8871
Several classes of voltage-gated Ca2+ channels (VGCCs) are inhibited b
y G proteins activated by receptors for neurotransmitters and neuromod
ulatory peptides, Evidence has accumulated to indicate that for non-L-
type Ca2+ channels the executing arm of the activated G protein is its
beta gamma dimer (G beta gamma). We report below the existence of two
G beta gamma-binding sites on the A-, B-, and E-type alpha(1) subunit
s that form non-L-type Ca2+ channels. One, reported previously, is in
loop 1 connecting transmembrane domains I and Il, The second is locate
d approximately in the middle of the ca, 600-aa-long C-terminal tails,
Both G beta gamma-binding regions also bind the Ca2+ channel beta sub
unit (CC beta), which, when overexpressed, interferes with inhibition
by activated G proteins, Replacement in alpha(1E) Of loop 1 with that
of the G protein-insensitive and G beta gamma-binding-negative loop 1
of alpha(1C) did not abolish inhibition by G proteins, but the exchang
e of the alpha(1E) C terminus with that of alpha(1C) did, This and pro
perties of alpha(1E) C-terminal truncations indicated that the G beta
gamma-binding site mediating the inhibition of Ca2+ channel activity i
s the one in the C terminus, Binding of G beta gamma to this site mas
inhibited by an alpha(1)-binding domain of CC beta, thus providing an
explanation for the functional antagonism existing between CC beta and
G protein inhibition. The data do not support proposals that G beta g
amma inhibits alpha(1) function by interacting with the site located i
n the loop I-II linker, These results define the molecular mechanism b
y which presynaptic G protein-coupled receptors inhibit neurotransmiss
ion.