The long-range goal of the research program in this laboratory is to characterize the electrophysiological properties of the ionic currents in cardiac tissue and to provide an understanding of the role of intracellular second messengers in the regulation and/or modulation of these currents. The research proposal outlined here is specifically aimed at mechanistic studies of Ca2+ currents, K+ currents and gap junctions in isolated heart muscle cells and in the effects of intracellular messengers on the properties of these currents. Experiments will be peformed in which """"""""concentrtion jumps"""""""" of putative intracellular second messenges, e.g. H+, cAMP, cGMP, ATP and Ca2+, are made (from photolabile precursors) inside of cells under electrophysiological investigation. Whole-cell patch clamp recordings will be employed most extensively on isolated adult and neonatal atrial and ventricular myocytes; additional studies will also exploit conventional intracellular recording techniques. In studies of Ca2+ and K+ current regulation, single cells will be utilized; in studies of gap junctions, cell pairs, either obtained from the dissociation procedure or recontacted after dissociation, will be used. These studies should permit determination of the kinetics and concentration dependences of intracellular messenger-mediated effects on macroscopic currents. In addition, later studies are aimed at evaluation of the influence(s) of intracellular messengers on the permeability of gap junctions as well as on controlling the number of functional channels which form in a gap junction. Although likely to be beyond the scope of the present proposal, we anticipate that the approaches employed will later be readily extended to studies of the mechanistic details of intracellular messenger-mediated modulation of ion channels at the single-channel level also employing patch-clamp recording techniques. It is unlikely that any direct clinical applications would result from the proposed experiments or from our work in general. It is anticipated, however, that these studies will provide insight into how the various cardiac membrane ion channels function normally as well as how they can be (and/or are) regulated and modulated by intracellular signals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL034161-01A1
Application #
3346818
Study Section
Physiology Study Section (PHY)
Project Start
1986-04-01
Project End
1989-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Johnson, Eric K; Matkovich, Scot J; Nerbonne, Jeanne M (2018) Regional Differences in mRNA and lncRNA Expression Profiles in Non-Failing Human Atria and Ventricles. Sci Rep 8:13919
Shih, Ying-Chun; Chen, Chao-Ling; Zhang, Yan et al. (2018) Endoplasmic Reticulum Protein TXNDC5 Augments Myocardial Fibrosis by Facilitating Extracellular Matrix Protein Folding and Redox-Sensitive Cardiac Fibroblast Activation. Circ Res 122:1052-1068
Lai, Chun-Fu; Chen, Yen-Ting; Gu, Jian et al. (2018) Circulating long noncoding RNA DKFZP434I0714 predicts adverse cardiovascular outcomes in patients with end-stage renal disease. Int J Cardiol :
Johnson, Eric K; Springer, Steven J; Wang, Wei et al. (2018) Differential Expression and Remodeling of Transient Outward Potassium Currents in Human Left Ventricles. Circ Arrhythm Electrophysiol 11:e005914
Burel, Sophie; Coyan, Fabien C; Lorenzini, Maxime et al. (2017) C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation. J Biol Chem 292:17431-17448
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Hueneke, Rocco; Adenwala, Adam; Mellor, Rebecca L et al. (2017) Early remodeling of repolarizing K+ currents in the ?MHC403/+ mouse model of familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 103:93-101
Khandekar, Aditi; Springer, Steven; Wang, Wei et al. (2016) Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents. Circ Res 119:1324-1338
Yang, Kai-Chien; Nerbonne, Jeanne M (2016) Mechanisms contributing to myocardial potassium channel diversity, regulation and remodeling. Trends Cardiovasc Med 26:209-18
Nerbonne, Jeanne M (2016) Molecular Basis of Functional Myocardial Potassium Channel Diversity. Card Electrophysiol Clin 8:257-73

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