Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 2, Pages 907-912Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.97.2.907
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- NIGMS NIH HHS [GM 56180] Funding Source: Medline
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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 G(o) and G(i)). To date, however, the composition of heterotrimeric complexes, i.e., specific G alpha beta gamma combinations, capable of coupling receptors to N-type Ca2+ channels has not been defined. We addressed this question by heterologously expressing identified G alpha beta gamma combinations in PTX-treated rat sympathetic neurons and testing for reconstitution of agonist-mediated VD inhibition. The heterologously expressed G alpha 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 G alpha(oA), G alpha(oB), and G alpha(i2) (along with G beta(1 gamma 2)) reconstituted VD inhibition mediated by alpha(2)-adrenergic, adenosine, somatostatin, and prostaglandin E-2 receptors. Conversely, expression of G alpha(i1) and G alpha(i3) was ineffective at restoring coupling. (ii) Coupling efficiency, as determined from the magnitude of reconstituted Ca2+ current inhibition, depended on both the receptor and G alpha subtype. The following rank order of coupling efficiency was observed: G alpha(oA) = G alpha(oB) > G alpha(i2) for alpha(2)-adrenergic receptor; C alpha(i2) > G alpha(oA),n = G alpha(oB) for adenosine and prostaglandin E-2 receptors; and G alpha(oB) = G alpha(i2) > G alpha(oA) for the somatostatin receptor. (iii) In general, varying the G beta gamma composition of G alpha(oA)-containing heterotrimers had little effect on the coupling of alpha(2)-adrenergic receptors to the VD pathway. Taken together, these results suggest that multiple, diverse Gapy combinations are capable of coupling neurotransmitter receptors to VD inhibition of N-type Ca2+ channels. Thus, if exquisite G alpha beta gamma-coupling specificity exists in situ, it cannot arise solely from the inherent inability of other G alpha beta gamma combinations to form functional signaling complexes.
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