Hypertension is a cardiovascular disease associated with increased plasma catecholamines, overactivation of the sympathetic nervous system, and increased vascular tone and total peripheral resistance. A key regulator of sympathetic nervous system function is the ␣ 1D -adrenergic receptor (AR), which belongs to the adrenergic family of G-protein-coupled receptors (GPCRs). Endogenous catecholamines norepinephrine and epinephrine activate ␣ 1D -ARs on vascular smooth muscle to stimulate vasoconstriction, which increases total peripheral resistance and mean arterial pressure. Indeed, ␣ 1D -AR KO mice display a hypotensive phenotype and are resistant to salt-induced hypertension. Unfortunately, little information exists about how this important GPCR functions because of an inability to obtain functional expression in vitro. Here, we identified the dystrophin proteins, syntrophin, dystrobrevin, and utrophin as essential GPCR-interacting proteins for ␣ 1D -ARs. We found that dystrophins complex with ␣ 1D -AR both in vitro and in vivo to ensure proper functional expression. More importantly, we demonstrate that knock-out of multiple syntrophin isoforms results in the complete loss of ␣ 1D -AR function in mouse aortic smooth muscle cells and abrogation of ␣ 1D -AR-mediated increases in blood pressure. Our findings demonstrate that syntrophin and utrophin associate with ␣ 1D

The G-protein-coupled receptor (GPCR) GPR54 is essential for the development and maintenance of reproductive function in mammals. A point mutation (L148S) in the second intracellular loop (IL2) of GPR54 causes idiopathic hypogonadotropic hypogonadism, a disorder characterized by delayed puberty and infertility. Here, we characterize the molecular mechanism by which the L148S mutation causes disease and address the role of IL2 in Class A GPCR function. Biochemical, immunocytochemical, and pharmacological analysis demonstrates that the mutation does not affect the expression, ligand binding properties, or protein interaction network of GPR54. In contrast, diverse GPR54 functional responses are markedly inhibited by the L148S mutation. Importantly, the leucine residue at this position is highly conserved among class A GPCRs. Indeed, mutating the corresponding leucine of the ␣ 1A -AR recapitulates the effects observed with L148S GPR54, suggesting the critical importance of this hydrophobic IL2 residue for Class A GPCR functional coupling. Interestingly, co-immunoprecipitation studies indicate that L148S does not hinder the association of G␣ subunits with GPR54. However, fluorescence resonance energy transfer analysis strongly suggests that L148S impairs the ligand-induced catalytic activation of G␣. Combining our data with a predictive Class A GPCR/G␣ model suggests that IL2 domains contain a conserved hydrophobic motif that, upon agonist stimulation, might stabilize the switch II region of G␣. Such an interaction could promote opening of switch II of G␣ to facilitate GDP-GTP exchange and coupling to downstream signaling responses. Importantly, mutations that disrupt this key hydrophobic interface can manifest as human disease.A diverse network of signaling pathways have evolved within the hypothalamic-pituitary-gonadal axis to ensure precise neuroendocrine regulation of reproductive function in mammals (1). An essential feature of this physiological system is the pulsatile release of gonadotropin-releasing hormone from hypothalamic neurons, which subsequently initiates follicle-stimulating hormone and luteinizing hormone release from the pituitary and ultimately impinges on the gonads to elicit sex steroid secretion (2). Together, the components of the hypothalamic-pituitary-gonadal axis function with precise temporal and spatial accuracy to regulate the development and maintenance of proper reproductive function, including puberty onset and the estrous cycle (3). Thus, functional mutations in key elements of this critical physiological system can result in the development of various reproductive disorders. For example, idiopathic hypogonadotropic hypogonadism (IHH), 2 which is characterized by delayed or absent puberty, immature reproductive organs, low levels of sex steroids and infertility, is commonly associated with loss-of-function mutations in the gonadotropin-releasing hormone receptor (4, 5). More recently, IHH-causing mutations were identified in a relatively uncharacterized orphan G-protein-coupled recep...

NMS mortality rates have declined over the past 30 years, most likely due to early recognition of the syndrome and appropriate intervention. Nonetheless, clinicians, especially primary care clinicians who are using this class of drugs more often for adjunctive treatments, must be cognizant of this syndrome and the implications of their use.​.

The purpose of this study was to develop and test two interventions designed to improve provider compliance with diabetes management guidelines: the use of a diabetes management flowsheet inserted into patient charts and the use of a diabetes management flowsheet plus quarterly provider feedback about compliance levels. Diabetic patient charts from six family practice clinics were randomly selected and audited at baseline and at 12 months. The analysis indicated that the use of the flowsheet was associated with improved provider compliance in the completion of foot examinations only. Providers involved in the study believed that the process of the flowsheet plus feedback contributed to their greater awareness of diabetes management guidelines.

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