The focus of my research is to investigate the mechanism of the perivascular nerve Ca2+-sensing receptor (CaR)-mediated vasodilation and its modulation by hypertension. Earlier studies indicate that extracellular calcium (Ca2+e) induced relaxation of isolated mesenteric resistance arteries pre-contracted with phenylephrine. This process is dependent on an intact perivascular sensory nerve network. We hypothesized that elevation of Ca2+e in the interstitial compartment activates the sensory nerve CaR and leads to the production and release of a vasodilator compound(s) that induce relaxation. We have also shown that mesenteric arteries from salt-sensitive rats and mice expressing the heterozygous receptor (CaR+/-) have impaired Ca2+e-induced relaxation suggesting a defect in the CaR signaling pathway in these animals. Therefore, understanding the Ca2+e-induced signaling mechanism of CaR and its modulation by salt and hypertension is important in identifying this receptor as a target for the development of new anti-hypertensive therapy.
We employ state-of-the-art biochemical, pharmacological and molecular biology techniques to characterize the signal transduction mechanisms of this novel receptor, expressed as a green fluorescent (EGFP) fusion protein, that lead to vasodilation. These studies may lead to the understanding of the molecular mechanisms linking Ca2+ homeostasis and vascular function. Our findings may provide the basis for the development of novel pharmacologic means of regulating blood pressure that could have significant impact on minority populations in particular.
1. Lakeesha E. Bridges Research Technician
2. Cicely L. Williams Research Technician
1. Nicole Villanueva Undergraduate Student
2. Samora Rugumamu Graduate Student
3. Linda Okeiyi Graduate Student
Publications by Emmanuel M Awumey
Earlier publications: Derfoul A, Lin FJ, Awumey EM, Kolodzeski T, Hall DJ, Tuan RS. Estrogenic endocrine disruptive components interfere with calcium handling and differentiation of human trophoblast cells. J. Cell Biochem 89: 755-770, 2003.
Wang Y, Awumey EK, Chatterjee PK, Somasundaram C, Bian K, Rogers KV, Dunn C, Bukoski RD. Molecular cloning and characterization of a rat sensory nerve Ca2+-sensing Receptor. Am J. Physiol Cell Physiol 285: C64-C75, 2003.
Awumey EM, Howlett AC, Diz DI. Commentry: Is there a role for anandamide in cardiovascular regulation? Insights from studies of endocannabinoid metabolism. Am J Physiol Heart Circ Physiol 289: H520-H521, 2005.
Awumey EM, Bukoski RD. Cellular Functions and Fluxes of Calcium. In: Weaver CM, Heaney RP, eds. Calcium in Human Health, Totowa, NJ: Humana Press, Chp. 3, pp. 13-25, 2006.
Awumey EM, Howlett AC, Diz DI, Putney JW, Jr., Bukoski RD. Ca2+ mobilization through the Dorsal Root Ganglion Ca2+-sensing receptor stably expressed in HEK293 cells. Am J. Physiol Cell Physiol 292: C1895-C1905, 2007.
Heyeraas KJ, Haug SR, Bukoski RD, Awumey EM. Identification of the Ca2+-sensing Receptor in Rat Trigeminal Ganglia, Sensory Axons and Tooth Dental Pulp. Calc.Tissue Int.85: 57-65, 2008.
Awumey EM, Hill SK, Diz DI, Bukoski RD. Cytochrome P450 metabolites of 2-arachidonyl glycerol play a role in Ca2+-induced relaxation of isolated mesenteric arteries. Am J Physiol Heart Circ Physiol. 294: H2363-H2370, 2008.
Sesay J, Somasundaram C, Diz DI, Bukoski RD, Howlett AC Awumey EM. N18TG2 neuroblastoma cells express a Ca2+-sensing receptor coupled to intracellular Ca2+ signalling. Submitted.
Bukoski RD, Somasundaram C, Cogdell K, Howlett A, Awumey EM. N18TG2 cells express a Ca2+-sensing receptor coupled with intracellular Ca2+ signaling. Hypertension 42: P31, 2003.
Awumey EM, Bukoski RD. The IP3 receptor antagonist, 2-aminoethoxydiphenyl borate blocks [Ca2+]i transients and store-operated calcium entry in HEK293 cells expressing the sensory nerve Ca2+-sensing receptor. FASEB J. 18: A970, 2004.
Awumey EM, Putney JW, Jr., Howlett A, Bukoski RD. Desensitization of the sensory nerve Ca2+-sensing receptor stably expressed in HEK293 cells is mediated by protein kinase C. FASEB J. 19: A524, 2005.
Awumey EM, Hill SK, Diz DI, Bukoski RD. 2-Arachidonylglycerol and its metabolite, glycerated epoxy-eicosatrienoic acid mediate Ca2+-induced relaxation of isolated mesenteric arteries. Am J Hypertension 18: 50A, 2005.
Awumey EM, Hill SK, Kunos G, Diz DI, Bukoski RD. Ionized calcium, in the physiological range, induces the release and metabolism of anandamide and 2-arachidonyl glycerol in isolated mesenteric artery arcade. Hypertension 46: P21, 2005.
Awumey EM, Diz DI, Howlett AC, Putney JW, Jr. Downregulation of protein kinase C Inhibits perivascular sensory nerve Ca2+-sensing receptor signaling. Hypertension 48: E85, 2006.
Heyeraas KJ, Haug SR, Awumey EM. Identification of the Ca2+-sensing receptor in rat trigeminal ganglia, sensory axons and tooth dental pulp. FASEB J 21: A73, 2007.
Sesay J, Howlett AC, Diz DI, Awumey EM. Ca2+-sensing receptor signaling in mouse neuroblastoma cells: A model for the perivascular sensory nerve Ca2+-sensing receptor. Hypertension 50:e124, 2007.