Effect of G protein heterotrimer composition on coupling of neurotransmitter receptors to N-type Ca2+ channel modulation in sympathetic neurons

AUTOR(ES)

Jeong, Seong-Woo

FONTE

The National Academy of Sciences

RESUMO

Voltage-dependent (VD) inhibition of N-type Ca2+ channels is mediated primarily by neurotransmitter receptors that couple to pertussis toxin (PTX)-sensitive G proteins (such as Go and Gi). To date, however, the composition of heterotrimeric complexes, i.e., specific Gαβγ combinations, capable of coupling receptors to N-type Ca2+ channels has not been defined. We addressed this question by heterologously expressing identified Gαβγ combinations in PTX-treated rat sympathetic neurons and testing for reconstitution of agonist-mediated VD inhibition. The heterologously expressed Gα subunits were rendered PTX-insensitive by mutating the codon specifying the ADP ribosylation site. The following results were obtained from this approach. (i) Expression of GαoA, GαoB, and Gαi2 (along with Gβ1γ2) reconstituted VD inhibition mediated by α2-adrenergic, adenosine, somatostatin, and prostaglandin E2 receptors. Conversely, expression of Gαi1 and Gαi3 was ineffective at restoring coupling. (ii) Coupling efficiency, as determined from the magnitude of reconstituted Ca2+ current inhibition, depended on both the receptor and Gα subtype. The following rank order of coupling efficiency was observed: GαoA = GαoB > Gαi2 for α2-adrenergic receptor; Gαi2 > GαoA = GαoB for adenosine and prostaglandin E2 receptors; and GαoB = Gαi2 > GαoA for the somatostatin receptor. (iii) In general, varying the Gβγ composition of GαoA-containing heterotrimers had little effect on the coupling of α2-adrenergic receptors to the VD pathway. Taken together, these results suggest that multiple, diverse Gαβγ combinations are capable of coupling neurotransmitter receptors to VD inhibition of N-type Ca2+ channels. Thus, if exquisite Gαβγ-coupling specificity exists in situ, it cannot arise solely from the inherent inability of other Gαβγ combinations to form functional signaling complexes.

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