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Biophys J, April 2000, p. 1895-1905, Vol. 78, No. 4

pH Modification of Human T-Type Calcium Channel Gating

Brian P. Delisle and Jonathan Satin

Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0298 USA

External pH (pHo) modifies T-type calcium channel gating and permeation properties. The mechanisms of T-type channel modulation by pH remain unclear because native currents are small and are contaminated with L-type calcium currents. Heterologous expression of the human cloned T-type channel, alpha 1H, enables us to determine the effect of changing pH on isolated T-type calcium currents. External acidification from pHo 8.2 to pHo 5.5 shifts the midpoint potential (V1/2) for steady-state inactivation by 11 mV, shifts the V1/2 for maximal activation by 40 mV, and reduces the voltage dependence of channel activation. The alpha 1H reversal potential (Erev) shifts from +49 mV at pHo 8.2 to +36 mV at pHo 5.5. The maximal macroscopic conductance (Gmax) of alpha 1H increases at pHo 5.5 compared to pHo 8.2. The Erev and Gmax data taken together suggest that external protons decrease calcium/monovalent ion relative permeability. In response to a sustained depolarization alpha 1H currents inactivate with a single exponential function. The macroscopic inactivation time constant is a steep function of voltage for potentials < -30 mV at pHo 8.2. At pHo 5.5 the voltage dependence of tau inact shifts more depolarized, and is also a more gradual function of voltage. The macroscopic deactivation time constant (tau deact) is a function of voltage at the potentials tested. At pHo 5.5 the voltage dependence of tau deact is simply transposed by ~40 mV, without a concomitant change in the voltage dependence. Similarly, the delay in recovery from inactivation at Vrec of -80 mV in pHo 5.5 is similar to that with a Vrec of -120 mV at pHo 8.2. We conclude that alpha 1H is uniquely modified by pHo compared to other calcium channels. Protons do not block alpha 1H current. Rather, a proton-induced change in activation gating accounts for most of the change in current magnitude with acidification.

Biophys J, April 2000, p. 1895-1905, Vol. 78, No. 4
© 2000 by the Biophysical Society   0006-3495/00/04/1895/11  $2.00


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