Cloning and Expression of a Novel Member of the Low Voltage-Activated T-Type Calcium Channel Family

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Abstract
Low voltage-activated Ca2+ channels play important roles in pacing neuronal firing and producing network oscillations, such as those that occur during sleep and epilepsy. Here we describe the cloning and expression of the third member of the T-type family, α1I or CavT.3, from rat brain. Northern analysis indicated that it is predominantly expressed in brain. Expression of the cloned channel in either Xenopusoocytes or stably transfected human embryonic kidney-293 cells revealed novel gating properties. We compared these electrophysiological properties to those of the cloned T-type channels α1G and α1H and to the high voltage-activated channels formed by α1Eβ3. The α1I channels opened after small depolarizations of the membrane similar to α1G and α1H but at more depolarized potentials. The kinetics of activation and inactivation were dramatically slower, which allows the channel to act as a Ca2+ injector. In oocytes, the kinetics were even slower, suggesting that components of the expression system modulate its gating properties. Steady-state inactivation occurred at higher potentials than any of the other T channels, endowing the channel with a substantial window current. The α1I channel could still be classified as T-type by virtue of its criss-crossing kinetics, its slow deactivation (tail current), and its small (11 pS) conductance in 110 mm Ba2+ solutions. Based on its brain distribution and novel gating properties, we suggest that α1I plays important roles in determining the electroresponsiveness of neurons, and hence, may be a novel drug target.