The arterial baroreceptors are sensory endings restricted to the carotid sinus and aortic arch but with powerful regulatory influences. They transduce arterial pressure signals into neurohumoral regulation of cardiovascular structure and homeostasis. Despite a large amount of information on the determinants of activation of baroreceptor (BR) nerves, the molecular, cellular and functional determinants of mechanoelectrical transduction at their sensory nerve endings are largely unknown. Project IV of this PPG addresses the neurobiology of mechanosensation. This Project (IV.A.1) which was initiated four years ago, as focused on 1) the identification of BR neurons in the nodose ganglion; 2) culturing them in vitro; 3) the development of a quantitative system for their mechanical activation; and 4) the definition of their responses with measurements of whole cell membrane currents, single-channel openings [Ca2+]i. A functional correlate of the cellular mechanisms was sought by measurements of carotid sinus nerve activity in vivo. Based on very exciting preliminary studies, we now propose to test the hypothesis that the ENaC/degenerin family of proteins represent ionic channel responsible for mechanoelectrical transduction in BR neurons. This hypothesis gains a strong rationale from the discovery of a genetic link between touch sensation in C. Elegans and the evidence of mechanical activation of ENaC/degenerin channels. In preliminary studies we found that 1) the subunits of ENAC/degenerin, gamma ENaC; beta ENaC and BNC1 (recently cloned from brain), are expressed in the aortic arch adventitia in the nodose ganglia where the BR nerve terminals and BR neurons are located, respectively; 2) the activity of BNC1a (transfected into oocytes) is blocked by Gd3+, a known blocker of mechanosensory channels; and 3) the rise in [Ca2+]i in BR neurons during mechanical stimulation is blocked by amiloride, a known blocker of the ENaC/degenerin channels.
Our aims are: first, to identify ENaC/degenerin ENaC/degenerin channels; and third, to attempt to disrupt the BR responses to mechanical stimulation at the cellular, organ and whole animal level by transfection of dominant- negatives of ENaC/degenerin family. The uniqueness of the project is in the joining of two leading laboratories, with expertise in neurobiology of autonomic control (Abboud) and in the molecular biology of ion channels (Welsh). With the added support of excellent cores in imaging, transgenic animals, and gene transfer, the promise of successful pursuit of this problem is ascertained.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL014388-26
Application #
6272497
Study Section
Project Start
1998-03-06
Project End
1998-12-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
26
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Lane-Cordova, Abbi D; Kalil, Graziela Z; Wagner, Christopher J et al. (2018) Hemoglobin A1c and C-reactive protein are independently associated with blunted nocturnal blood pressure dipping in obesity-related prediabetes. Hypertens Res 41:33-38
Larson, Robert A; Chapleau, Mark W (2018) Increased cardiac sympathetic activity: Cause or compensation in vasovagal syncope? Clin Auton Res 28:265-266
Tong, Brian; Abosi, Oluchi; Schmitz, Samantha et al. (2018) Bipolar disorder and related mood states are not associated with endothelial function of small arteries in adults without heart disease. Gen Hosp Psychiatry 51:36-40
Zeng, Wei-Zheng; Marshall, Kara L; Min, Soohong et al. (2018) PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science 362:464-467
DuBose, Lyndsey E; Boles Ponto, Laura L; Moser, David J et al. (2018) Higher Aortic Stiffness Is Associated With Lower Global Cerebrovascular Reserve Among Older Humans. Hypertension 72:476-482
Holwerda, Seth W; Luehrs, Rachel E; Gremaud, Allene L et al. (2018) Relative burst amplitude of muscle sympathetic nerve activity is an indicator of altered sympathetic outflow in chronic anxiety. J Neurophysiol 120:11-22
Sabharwal, Rasna; Mason, Bianca N; Kuburas, Adisa et al. (2018) Increased receptor activity-modifying protein 1 in the nervous system is sufficient to protect against autonomic dysregulation and hypertension. J Cereb Blood Flow Metab :271678X17751352
Harwani, Sailesh C (2018) Macrophages under pressure: the role of macrophage polarization in hypertension. Transl Res 191:45-63
Shaffer Jr, Joseph J; Johnson, Casey P; Fiedorowicz, Jess G et al. (2018) Impaired sensory processing measured by functional MRI in Bipolar disorder manic and depressed mood states. Brain Imaging Behav 12:837-847
Xue, Baojian; Beltz, Terry G; Guo, Fang et al. (2018) Sex differences in maternal gestational hypertension-induced sensitization of angiotensin II hypertension in rat offspring: the protective effect of estrogen. Am J Physiol Regul Integr Comp Physiol 314:R274-R281

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