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1 Physiology & Biophysics, University of Calgary, Calgary, Alberta, Canada
2 Molecular and Cellular Pharmacology, Nagoya City University, Nagoya, Japan
3 St. Boniface Heart Institute, University of Manitoba, Winnipeg, Manitoba, Canada
4 Bioengineering, University of California San Diego, La Jolla, California, USA
* To whom correspondence should be addressed. E-mail: w.giles{at}bioeng.ucsd.edu.
Despite the important roles played by ventricular fibroblasts and myofibroblasts in formation and maintenance of the extracellular matrix, neither the ionic basis for membrane potential, nor the effect of modulating membrane potential on function, have been analyzed in detail. In this study, whole-cell patch clamp experiments were done using ventricular fibroblasts and myofibroblasts. Time- and voltage-dependent outward K+ currents were recorded at depolarized potentials, and an inwardly rectifying K+ (Kir) current was recorded near the resting membrane potential (RMP) and at more hyperpolarized potentials. The apparent reversal potential of Kir currents shifted to more positive potentials as external K+ concentration ([K+]o) was raised and this Kir current was blocked by 100 - 300 micromolar Ba2+. RT-PCR measurements showed that mRNA for Kir2.1 was expressed. Accordingly, we conclude that Kir current is the primary determinant of RMP in both fibroblasts and myofibroblasts. Changes in [K+]o influenced fibroblast membrane potential as well as proliferation and contractile functions. Recordings made with a voltage-sensitive dye, DiBAC3(4), showed that 1.5 mM [K+]o resulted in a hyperpolarization, while 20 mM [K+]o produced a depolarization. Low [K+]o (1.5 mM) enhanced myofibroblast number relative to control (5.4 mM [K+]o). In contrast, 20 mM [K+]o resulted in a significant reduction in myofibroblast number. In separate assays, 20 mM [K+]o significantly enhanced contraction of collagen I gels seeded with myofibroblasts, compared to control mechanical activity in 5.4 mM [K+]o. In combination these results show that ventricular fibroblasts and myofibroblasts express a variety of K+ channel alpha subunits and demonstrate that Kir current can modulate RMP and alter essential physiological functions.
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