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

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Abstract: α1D-adrenergic receptors (ARs) are essential G protein-coupled receptors (GPCRs) of the sympathetic nervous system, and are a promising therapeutic target for an array of diseases. In the central nervous system, the α1D-AR tightly regulates stimulus-induced locomotor activity, and is 1 of 13 hypermethylated genes associated with decreased brain volume in schizophrenic patients. The α1D-AR is critical for blood pressure regulation and stenosis of damaged blood vessels. The receptor also can negatively impact urine flow by contracting the prostate in patients suffering from benign prostatic hypertrophy (BPH). Thus, α1-AR antagonists (“α-blockers”) are often used to treat hypertension, urinary incontinence, and most recently with promising success stories, to prevent reoccurring nightmares in combat veterans afflicted with Post-Traumatic Stress Disorder. Unfortunately, major toxicities can often occur in patients taking α-blockers. During the ALLHAT trial, α-blocker therapy was discontinued due to increased patient morbidity. Accordingly, a clearer picture of how the α1D-AR engages with its cellular environment will provide critical insights towards the further development of small molecule α1D-AR modulators beneficial for the treatment of PTSD, BPH, and cardiovascular disease. Surprisingly, our basic knowledge of α1D-AR biochemical processes is lacking within human contexts, primarily because no human cell lines have been identified that express endogenous α1D-ARs. Without adequate cell culture models and human model cell systems to examine their discrete biochemical interactions, it will continue to be challenging to develop new small molecules targeting α1D-ARs and to understand their essential molecular and cellular functions. We have made significant progress towards solving some of these mysteries. First, we discovered that α1D-ARs interact with multiple PSD95/DLG1/Zo-1 (PDZ) domain-containing proteins. Second, we found these interactions are essential for α1D-ARs to be expressed as functional receptors at the plasma membrane. Remarkably, we found that α1D-ARs interact with two PDZ- proteins, syntrophin and scribble, in all human cell lines we examined. This novel discovery provides an opportunity to develop small molecule allosteric ligands targeting α1D-AR:PDZ-protein interaction-interfaces. However, this first requires a thorough characterization of α1D-AR:PDZ-protein architecture and function. In this competing renewal, we propose to extend our findings in new directions using the following aims. Aim 1: Determine whether scribble organizes α1D-ARs into signaling clusters. Aim 2: Identify α1D-AR:PDZ-protein complex(es) in human cells. This proposal has the overarching goal of targeting discrete α1D-AR:PDZ-protein interfaces with novel small molecules to treat diseases associated with aberrant α1D-AR signaling.