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; and negatively impacts 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, 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. The initial aims we that were proposed were the following: Aim 1: Determine whether scribble organizes α1D-ARs into signaling clusters. Aim 2: Identify α1D-AR:PDZ-protein complex(es) in human cells.