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Publications (3)10.67 Total impact

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    ABSTRACT: Microvascular diseases, such as retinopathies, neuropathies, and nephropathies, are a devastating consequence of type 1 and type 2 diabetes. The etiology of diabetes-associated microvascular dysfunction is poorly understood, and, likewise, treatment modalities for these disorders are limited. Interestingly, proinsulin C-peptide has been shown to play a protective role against diabetes-associated complications in experimental animals and in diabetic humans and is thus an attractive therapeutic target. However, an important step in the development of C-peptide-based therapeutics is identification of the C-peptide receptor, which is likely a G protein-coupled receptor (GPCR). Using a unique Deductive Ligand-Receptor Matching Strategy, we sought to determine whether one of the known orphan GPCRs is essential for C-peptide signaling. Knockdown of GPR146, but not GPR107 or GPR160, blocked C-peptide-induced cFos expression in KATOIII cells. Furthermore, stimulation with C-peptide caused internalization of GPR146, and examples of punctate colocalization were observed between C-peptide and GPR146 on KATOIII cell membranes. These data indicate that GPR146 is likely a part of the C-peptide signaling complex and provide a platform for the elucidation of the C-peptide signalosome.
    Journal of Endocrinology 01/2013; 218(2):B1-8. · 4.06 Impact Factor
  • Gina L C Yosten, Lauren J Redlinger, Willis K Samson
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    ABSTRACT: Neuronostatin, derived from the somatostatin preprohormone, is a recently described peptide that is produced by several tissues involved in cardiovascular regulation and metabolism, including the hypothalamus. Central injection of neuronostatin led to a dose-related increase in mean arterial pressure (MAP) in rats. Any attempt to inhibit the production of neuronostatin would alter somatostatin production as well, making determination of the physiologic relevance of the peptide's pharmacologic effects by compromise of production approaches impossible. We therefore employed an alternative approach-to identify and compromise the production of the neuronostatin receptor. Because neuronostatin was shown to signal via a PKA-dependent mechanism, we hypothesized that the neuronostatin receptor was a G protein-coupled receptor (GPCR), in particular, one of the orphan GPCRs for which the ligand is unknown. We therefore screened neuronostatin-responsive tissues, including hypothalamus, heart, pancreatic alpha cells, and the gastric tumor cell line KATOIII, for expression of non-odorant orphan GPCRs. Four orphan GPCRs were expressed by all cell types, including GPR56 and GPR107. Knockdown of GPR107, but not GPR56, led to a loss of responsiveness to neuronostatin by KATOIII cells. Rats injected centrally with siRNA directed against GPR107 did not exhibit an increase in MAP in response to neuronostatin treatment. Rats with compromised GPR107 expression also displayed blunted reactivity in a baroreflex sensitivity test, indicating that GPR107, and neuronostatin, may be important regulators of cardiovascular function. Thus GPR107 is a promising candidate receptor for neuronostatin, and neuronostatin, interacting with GPR107, may play an important role in the central control of cardiovascular function.
    AJP Regulatory Integrative and Comparative Physiology 08/2012; · 3.28 Impact Factor
  • G L C Yosten, L Redlinger, W K Samson
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    ABSTRACT: Nesfatin-1, a post-translational product of the nucleobindin-2 (NucB2) gene, is produced in several brain areas known to be important in neuroendocrine, autonomic and metabolic function, including the hypothalamus and medulla. The hallmark action of the peptide is its ability at picomole doses to inhibit food and water intake in rodents and, indeed, the effect on water intake is more pronounced than that on food intake. In preliminary studies, we observed a decrease in hypothalamic NucB2 expression in response to overnight water deprivation even when food was present, which reversed when water was returned to the animals. We therefore hypothesised that the effect of nesfatin-1 on water drinking was independent of its anorexigenic action. Indeed, rats administered nesfatin-1 i.c.v. consumed significantly less water than controls in response to a subsequent, dipsogenic dose of angiotensin II, or upon return of water bottles after 18 h of fluid restriction (food present), or in response to a hypertonic challenge. Pretreatment with an antisense oligonucleotide against nesfatin-1 significantly reduced levels of immunoreactive nesfatin-1 in the hypothalamic paraventricular nucleus and resulted in exaggerated drinking responses to angiotensin II. The results obtained in the present study suggest that locally produced nesfatin-1 may be an important component of the hypothalamic mechanisms controlling fluid and electrolyte homeostasis.
    Journal of Neuroendocrinology 02/2012; 24(7):1078-84. · 3.33 Impact Factor