The a-catulin/dystrophin-associated protein complex regulates GPCR function

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DESCRIPTION (provided by applicant): α1-adrenergic receptors (ARs) are G-protein coupled receptors (GPCRs) that respond to sympathetic hormones norepinephrine and epinephrine, and are therapeutic targets for the treatment of hypertension, benign prostrate hypertrophy (BPH), and post-traumatic stress disorder (PTSD). α1-ARs comprise 3 unique subtypes, α1A, α1B, and α1D, which are ubiquitously expressed on blood vessels throughout the CNS. Although each subtype responds to norepinephrine/epinephrine and activates Gαq/11 signaling, the α1D-AR subtype performs a specialized role using mechanisms distinct from the α1A-AR and α1B-AR subtypes. For example, α1D-ARs stimulate vascular smooth muscle cell migration, while the α1A and α1B-AR subtypes stimulate vascular smooth cell hypertrophy. The molecular mechanisms that permit α1D-ARs to selectively activate pathways distinct from those used by the α1A and α1B-AR subtypes remains a major mystery in the field. Revealing the molecular mechanisms α1D- ARs use to stimulate vascular smooth cell migration will identify new drug targets to treat CNS blood vessel restenosis and atherosclerotic plaque formation, prevent migraine associated with malignant hypertension and reduce the potential for stroke and neuronal cell death.