Cardiovascular disease is a leading cause of morbidity and mortality. Estrogen has been proposed to have a protective effect. In addition to the interaction with two classical nuclear receptors, estrogen activates a non nuclear receptor, GPR30. Our long-term goal is to understand the role of GPR30 in estrogen-mediated neuronal effects. The objective of this application is to determine the role of GPR30 in cardiovascular regulation. Our central hypothesis is that estrogen acting on GPR30 located on neurons of the nucleus ambiguus increases vagal activity to the heart, which may be cardioprotective. Viewed in this context, GPR30 is a potential target for the development of novel cardiovascular therapeutic agents. We will use a multidisciplinary approach including immunohistochemistry, confocal imaging, in vivo monitoring of blood pressure and heart rate, fluorimetric measurement of cytosolic calcium and whole-cell patch-clamp recording to address the following aims. First, localization of GPR30 to cardiac preganglionic neurons of the nucleus ambiguus. Our preliminary results indicate that GPR30 is present in cholinergic neurons of the nucleus ambiguus. We will use retrograde labeling, single and double immunohistochemical staining to identify the presence of GPR30 in cardiac projecting neurons of the nucleus ambiguus and its colocalization with aromatase. Second, measurement of heart rate and blood pressure in response to GPR30 agonists in vivo. Our preliminary results indicate that microinjection of G-1, a specific GPR30 agonist, or 17-estradiol (E2) into the nucleus ambiguus produces bradycardia;the effect was abolished by prior administration of G-36, a GPR30 antagonist. In addition, pilot experiments indicate that intravenous administration of G-1 and E2 decreased mean arterial pressure and heart rate in urethane-anesthetized rats. We will determine the effect of intravenous administration of GPR30 agonists on blood pressure, heart rate and the participation of the vagus nerve in these responses. Third, electrophysiological response of GPR30 activation in single nucleus ambiguus neurons in vitro. Our preliminary results indicate that G-1 excites neurons from nucleus ambiguus. We will determine the effect of GPR30 agonists on membrane properties, evoked and spontaneous synaptic currents from nucleus ambiguus neurons using whole-cell patch-clamp recordings in brainstem slices. Fourth, define the calcium pathways involved in GPR30-mediated neuronal responses. Our preliminary results indicate that activation of GPR30 produces calcium mobilization from external and internal sources in cultured rat hypothalamic neurons;the effect was abolished by pretreatment with G-36. We will determine the calcium pools involved in GPR30 signaling in premotor cardiac vagal neurons. The result of this study will extend our understanding of the mechanisms of action of estrogen on neurons involved in cardiovascular regulation with implications for the development of effective therapeutic approaches in cardiovascular disorders.
We will study the role of a new estrogen receptor in the central control of cardiovascular function. A better understanding of the mechanisms of action of estrogen is critical for the development of new treatments for cardiovascular disease.
|Park, Soonhong; Ahuja, Malini; Kim, Min Seuk et al. (2016) Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV. EMBO Rep 17:266-78|
|Barr, Jeffrey L; Deliu, Elena; Brailoiu, G Cristina et al. (2015) Mechanisms of activation of nucleus accumbens neurons by cocaine via sigma-1 receptor-inositol 1,4,5-trisphosphate-transient receptor potential canonical channel pathways. Cell Calcium 58:196-207|
|Brailoiu, Eugen; Deliu, Elena; Sporici, Romeo A et al. (2014) HIV-1-Tat excites cardiac parasympathetic neurons of nucleus ambiguus and triggers prolonged bradycardia in conscious rats. Am J Physiol Regul Integr Comp Physiol 306:R814-22|
|Deliu, Elena; Brailoiu, G Cristina; Eguchi, Satoru et al. (2014) Direct evidence of intracrine angiotensin II signaling in neurons. Am J Physiol Cell Physiol 306:C736-44|
|Brailoiu, Gabriela Cristina; Deliu, Elena; Rabinowitz, Joseph E et al. (2014) Urotensin II promotes vagal-mediated bradycardia by activating cardiac-projecting parasympathetic neurons of nucleus ambiguus. J Neurochem 129:628-36|
|Brailoiu, G Cristina; Deliu, Elena; Marcu, Jahan et al. (2014) Differential activation of intracellular versus plasmalemmal CB2 cannabinoid receptors. Biochemistry 53:4990-9|
|Sharma, Vishnu Dutt; Lees, Julia; Hoffman, Nicholas E et al. (2014) Modulation of pyridinium cationic lipid-DNA complex properties by pyridinium gemini surfactants and its impact on lipoplex transfection properties. Mol Pharm 11:545-59|
|Brailoiu, G Cristina; Deliu, Elena; Altmann, Joseph B et al. (2014) Evidence for role of acid-sensing ion channels in nucleus ambiguus neurons: essential differences in anesthetized versus awake rats. J Comp Physiol B 184:753-61|
|Jha, Archana; Ahuja, Malini; Patel, Sandip et al. (2014) Convergent regulation of the lysosomal two-pore channel-2 by Mg²?, NAADP, PI(3,5)P? and multiple protein kinases. EMBO J 33:501-11|
|Brailoiu, G Cristina; Benamar, Khalid; Arterburn, Jeffrey B et al. (2013) Aldosterone increases cardiac vagal tone via G protein-coupled oestrogen receptor activation. J Physiol 591:4223-35|
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