The carboxyl terminus of the G protein α subunit is a key determinant of the fidelity of receptor activation. We have previously shown that the G(qα) subunit (α(q)) can be made to respond to α(i)-coupled receptors by replacing its carboxyl terminus with the corresponding α(i2), α(o), or α(z) residues. We now extend these findings in three ways: 1) carboxyl- terminal mutations of α(q)/α(i) chimeras show that the critical amino acids are in the -3 and -4 positions, 2) exchange of carboxyl termini between α(q) and α(s) allows activation by receptors appropriate to the carboxyl-terminal residues, and 3) we identify receptors that either do or do not activate the expected carboxyl-terminal chimeras (α(q)/α(i), α(q)/α(s), α(s)/α(q)). Replacement of the five carboxyl-terminal amino acids of α(q) with the α(s) sequence permitted an α(s)-coupled receptor (the V2 vasopressin receptor but not the β2-adrenergic receptor) to stimulate phospholipase C. Replacement of the five carboxyl-terminal amino acids of α(s) with residues of α(q) permitted certain α(q)-coupled receptors (bombesin and V1a vasopressin receptors but not the oxytocin receptor) to stimulate adenylyl cyclase. Thus, the relative importance of the G(α) carboxyl terminus in permitting coupling to a new receptor depends on the receptor with which it is paired. These studies refine our understanding and provide new tools with which to study the fidelity of receptor/G(α) activation.
|Number of pages||6|
|State||Published - Oct 1996|