Compartmentalization of Individual GsCoupled GPCRs to Membrane Subdomains

There is compelling evidence that Pt and P2ARs activate distinct G protein/effector pathways and evoke distinct regulatory controls that lead to subtype-specific differences in the regulation of cardiac contraction and hypertrophic growth programs (Steinberg and Brunton 2001). Functional differences between Pt and P2AR signaling have been attributed in part to subtype-specific targeting to distinct membrane compartments. P2ARs are detected exclusively in caveolae/lipid raft membranes and egress from this compartment upon activation, whereas P1ARs are detected in both caveolae and non-caveolae membranes and do not undergo a detectable translocation upon activation (Rybin et al. 2000). PAR subtype segregation to different intracellular compartments provides a mechanism to simultaneously facilitate PAR interactions with certain signaling partners, while restricting interactions with others. While caveolin-3 (a protein that oligomerizes and drives the formation of caveolae) contains an interaction motif that anchors and regulates the activity of many lipid-modified signaling proteins in caveolae, caveolin expression is not required for PAR localization to caveolae. Hence, this section will focus on other scaffolding proteins that interact with various components of the cAMP generating machinery and might contribute to specificity in the cAMP signaling pathway in cardiomyocytes.

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