Targeted disruption of the Ca2+ channel β3 subunit reduces N- and L-type Ca2+ channel activity and alters the voltage-dependent activation of P/Q-type Ca2+ channels in neurons

Yoon Namkung, Stephen M. Smith, Seong Beom Lee, Nataliya V. Skrypnyk, Hyung Lae Kim, Hemin Chin, Richard H. Scheller, Richard W. Tsien, Hee Sup Shin

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Abstract

In comparison to the well characterized role of the principal subunit of voltage-gated Ca2+ channels, the pore-forming, antagonist-binding α1, subunit, considerably less is understood about how β subunits contribute to neuronal Ca2+ channel function. We studied the role of the Ca2+ channel β3 subunit, the major Ca2+ channel β subunit in neurons, by using a gene-targeting strategy. The β3 deficient (β3-/-) animals were indistinguishable from the wild type (wt) with no gross morphological or histological differences. However, in sympathetic β3-/- neurons, the L- and N-type current was significantly reduced relative to wt. Voltage-dependent activation of P/Q-type Ca2+ channels was described by two Boltzmann components with different voltage dependence, analogous to the "reluctant" and "willing" states reported for N-type channels. The absence of the β3 subunit was associated with a hyperpolarizing shift of the "reluctant" component of activation. Norepinephrine inhibited wt and β3-/- neurons similarly but the voltage sensitive component was greater for N-type than P/Q-type Ca2+ channels. The reduction in the expression of N-type Ca2+ channels in the β3-/- mice may be expected to impair Ca2+ entry and therefore synaptic transmission in these animals. This effect may be reversed, at least in part, by the increase in the proportion of P/Q channels activated at less depolarized voltage levels.

Original languageEnglish (US)
Pages (from-to)12010-12015
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number20
DOIs
StatePublished - Sep 29 1998

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