Gßγ subunits colocalize with RNA polymerase II and regulate transcription in cardiac fibroblasts.

Gßγ subunits mediate many different signaling processes in various compartments of the cell, including the nucleus. To gain insight into the functions of nuclear Gßγ signaling, we investigated the functional role of Gßγ signaling in the regulation of GPCR-mediated gene expression in primary rat neonatal cardiac fibroblasts. We identified a novel, negative, regulatory role for the Gß1γ dimer in the fibrotic response. Depletion of Gß1 led to derepression of the fibrotic response at the mRNA and protein levels under basal conditions and an enhanced fibrotic response after sustained stimulation of the angiotensin II type I receptor. Our genome-wide chromatin immunoprecipitation experiments revealed that Gß1 colocalized and interacted with RNA polymerase II on fibrotic genes in an angiotensin II-dependent manner. Additionally, blocking transcription with inhibitors of Cdk9 prevented association of Gßγ with transcription complexes. Together, our findings suggest that Gß1γ is a novel transcriptional regulator of the fibrotic response that may act to restrict fibrosis to conditions of sustained fibrotic signaling. Our work expands the role for Gßγ signaling in cardiac fibrosis and may have broad implications for the role of nuclear Gßγ signaling in other cell types.

Gßγ signaling from an eponymous past to a specific future.

An abiding issue has been parsing out the cellular impact of multiple Gß and Gγ subtypes. In an article in this issue of Cell Systems, Masuho et al. use a system developed to probe how distinct Gßγ combinations respond to GPCR stimulation and adopt distinct trafficking itineraries in the cell.

Subtype-dependent regulation of Gßγ signalling.

G protein-coupled receptors (GPCRs) transmit information to the cell interior by transducing external signals to heterotrimeric G protein subunits, Gα and Gßγ subunits, localized on the inner leaflet of the plasma membrane. Though the initial focus was mainly on Gα-mediated events, Gßγ subunits were later identified as major contributors to GPCR-G protein signalling. A broad functional array of Gßγ signalling has recently been attributed to Gß and Gγ subtype diversity, comprising 5 Gß and 12 Gγ subtypes, respectively. In addition to displaying selectivity towards each other to form the Gßγ dimer, numerous studies have identified preferences of distinct Gßγ combinations for specific GPCRs, Gα subtypes and effector molecules. Importantly, Gß and Gγ subtype-dependent regulation of downstream effectors, representing a diverse range of signalling pathways and physiological functions have been found. Here, we review the literature on the repercussions of Gß and Gγ subtype diversity on direct and indirect regulation of GPCR/G protein signalling events and their physiological outcomes. Our discussion additionally provides perspective in understanding the intricacies underlying molecular regulation of subtype-specific roles of Gßγ signalling and associated diseases.