Abstract
The ß1‐adrenergic receptor (ß1‐AR) is a target for treatment of major cardiovascular diseases such as heart failure and hypertension, but the mechanisms of its trafficking are obscure. Recycling of agonist‐internalized ß1‐AR is dependent on two domains the PDZ in the C‐tail and Ser312 in the third intracellular loop. Cross‐talk between a complex composed of SAP97‐AKAP79/PKA that is tethered to the PDZ promoted the phosphorylation Ser312, which served as the recycling signal for this GPCR. Site‐directed mutagenesis of the ß1‐AR PDZ indicated that ß1‐AR recycling was inhibited by mutations in the PDZ that interfered with SAP97 binding and by the inhibition of PKA. The trafficking effects of short sequences differing in their PDZ architecture indicated that PDZs, which bound SAP97, facilitated the recycling of the ß1‐AR in a PKA‐sensitive manner. ß1‐AR chimera containing non‐PDZs derived from recycling other proteins, promoted rapid recycling of chimeric ß1‐AR in SAP97‐ and PKA‐independent manner. These data indicated that a roadmap for the trafficking of this GPCR could be constructed that involves three branches, one for ß1‐AR chimera that recycle in a “sequence‐dependent” manner, another for ß1‐AR chimera that recycle in a “sequence independent” manner and a third for “non‐recycling” ß1‐AR chimera. We will also show that inter conversion between these three trafficking highways is possible by subtle mutations in the ß1‐AR structure or milieu.Supported by NIH, HL‐085848.Grant Funding Source: Supported by NIH, HL‐085848
Published Version
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