Subunit Regulation of the Human Brain α 1E Calcium Channel

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Abstract
The α1 subunit coding for the human brain type E calcium channel (Schneider et al., 1994) was expressed in Xenopus oocytes in the absence, and in combination with auxiliary α2δ and β subunits. α1E channels directed with the expression of Ba2+ whole-cell currents that completely inactivated after a 2-sec membrane pulse. Coexpression of α1E with α2bδ shifted the peak current by +10 mV but had no significant effect on whole-cell current inactivation. Coexpression of α1E with β2a shifted the peak current relationship by −10 mV, and strongly reduced Ba2+ current inactivation. This slower rate of inactivation explains that a sizable fraction (40 ± 10%, n= 8) of the Ba2+ current failed to inactivate completely after a 5-sec prepulse. Coinjection with both the cardiac/brain β2a and the neuronal α2bδ subunits increased by ≈10-fold whole-cell Ba2+ currents although coinjection with either β2a or α2bδ alone failed to significantly increase α1E peak currents. Coexpression with β2a and α2bδ yielded Ba2+ currents with inactivation kinetics similar to the β2a induced currents, indicating that the neuronal α2bδ subunit has little effect on α1E inactivation kinetics. The subunit specificity of the changes in current properties were analyzed for all four β subunit genes. The slower inactivation was unique to α1E/β2a currents. Coexpression with β1a, β1b, β3, and β4, yielded faster-inactivating Ba2+ currents than currents recorded from the α1E subunit alone. Furthermore, α1E/α2bδ/β1a; α1E/α2bδ/β1b; α1E/α2bδ/β3; α1E/α2bδ/β4 channels elicited whole-cell currents with steady-state inactivation curves shifted in the hyperpolarized direction. The β subunit-induced changes in the properties of α1E channel were comparable to modulation effects reported for α1C and α1A channels with β3≈β1b > β1a≈β4≫β2a inducing fastest to slowest rate of whole-cell inactivation.

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