Received for publication March 22, 2007.
Revised September 7, 2007.
Accepted for publication September 10, 2007.

Alternative translation initiation of human RGS2 yields a set of functionally distinct proteins

Abstract

The regulator of G-protein signaling RGS2 contains a characteristic RGS domain flanked by short amino and carboxyl terminal sequences. The RGS domain mediates inhibition of G_q and G_i signaling, while the amino terminal domain (NTD) directs interaction with adenylyl cyclases, GPCRs and other signaling partners. Here, we identify a set of novel RGS2 protein products that differ with respect to their amino terminal architecture and functional characteristics. An RGS2 expression reporter cassette revealed four distinct open reading frames that can be expressed from the RGS2 NTD. We hypothesized that alternative translation initiation from four AUG codons corresponding to amino acid positions 1, 5, 16, and 33 could produce the observed RGS2 expression profile. Selective disruption of each AUG confirmed that alternate sites of translation initiation accounted for each of the observed products. Proteins derived from ORFs 1-4 showed no difference in G_q inhibitory potential or recruitment from the nucleus in response to G_q signaling. By contrast, RGS2 products initiating from methionines at positions 16 (ORF3) and 33 (ORF4) were impaired as inhibitors of type V adenylyl cyclase (ACV) compared to full length RGS2. We predicted that regulation of the RGS2 expression profile would allow cells to adapt to changing signaling conditions. Consistent with this model, activation of G_s/ ACV but not G_q signaling increased the relative abundance of the full-length RGS2 protein suggesting that alternative translation initiation of RGS2 is part of a novel negative feedback control pathway for adenylyl cyclase signaling.

Key words: Gs family, Gq/11 family, Adenylyl cyclases, cAMP, IP3/DAG, Calcium (G Protein Coupled Signals), RGS proteins

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