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Vol. 61, Issue 3, 682-694, March 2002
Departments of Pharmacology (G.M., J.M., R.H., U.K., F.G., S.H.)
and Neurophysiology (A.P., T.S.), University of Cologne, Cologne,
Germany; Department of Medicine, Cardiovascular Institute, Loyola
University, Maywood, Illinois (L.L.C.); and Department of Pharmacology,
University of Virginia, Charlottesville, Virginia (E.P-R.)
To study the molecular pharmacology of low-voltage-activated calcium
channels in biophysical detail, human medullary thyroid carcinoma
(hMTC) cells were investigated using the single-channel technique.
These cells had been reported to express T-type whole-cell currents and
a Cav3.2 (or 
1H) channel subunit. We observed two types
of single-channel activity that were easily distinguished based on
single-channel conductance, voltage dependence of activation, time
course of inactivation, rapid gating kinetics, and the response to the
calcium agonist (S)-Bay K 8644. Type II channels had
biophysical properties (activation, inactivation, conductance) typical
for high-voltage-activated calcium channels. They were markedly
stimulated by 1 µM (S)-Bay K 8644, allowing to
identify them as L-type channels. The channel termed type I is a
low-voltage-activated, small-conductance (7.2 pS) channel that
inactivates rapidly and is not modulated by (S)-Bay K
8644. Type I channels are therefore classified as T-type channels. They
were strongly inhibited by 10 µM mibefradil. Mibefradil block was
caused by changes in two gating parameters: a pronounced reduction in
fraction of active sweeps and a slight shortening of the open-state
duration. Single recombinant low-voltage-activated T-type calcium
channels were studied in comparison, using human embryonic kidney 293 cells overexpressing the pore-forming Cav3.2 subunit. Along
all criteria examined (mechanisms of block, extent of block),
recombinant Cav3.2 interact with mibefradil in the same way
as their native counterparts expressed in hMTC cells. In conclusion,
the pharmacologic phenotype of these native human T-type channels
as
probed by mibefradilis similar to recombinant human
Cav3.2.
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