pH modification of human T-type calcium channel gating

External pH (pH(o)) 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 pH(o) 8.2 to pH(o) 5.5 shifts the midpoint potential (V-1/2) for steady-state inactivation by 11 mV, shifts the V-1/2 for maximal activation by 40 mV, and reduces the Voltage dependence of channel activation. The alpha 1H reversal potential (E-rev) shifts from +49 mV at pH(o) 8.2 to +36 mV at pH(o) 5.5. The maximal macroscopic conductance (G(max)) of alpha 1H increases at pH(o) 5.5 compared to pH(o) 8.2, The E-rev and G(max) 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 pH(o) 8.2. At pH(o) 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 pH(o) 5.5 the voltage dependence of tau(deatct) is simply transposed by similar to 40 mV, without a concomitant change in the voltage dependence. Similarly, the delay in recovery from inactivation at V-rec of -80 mV in pH(o) 5.5 is similar to that with a V-rec of -120 mV at pH(o) 8.2. We conclude that alpha 1H is uniquely modified by pH(o) 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.