title: Targeted disruption of the Ca2+ channel beta3 subunit reduces N- and L-type Ca2+ channel activity and alters the voltage-dependent activation of P/Q-type Ca2+ channels in neurons.
abstract: In comparison to the well characterized role of the principal subunit of voltage-gated Ca2+ channels, the pore-forming, antagonist-binding alpha1 subunit, considerably less is understood about how beta subunits contribute to neuronal Ca2+ channel function. We studied the role of the Ca2+ channel beta3 subunit, the major Ca2+ channel beta subunit in neurons, by using a gene-targeting strategy. The beta3 deficient (beta3-/-) animals were indistinguishable from the wild type (wt) with no gross morphological or histological differences. However, in sympathetic beta3-/- 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 beta3 subunit was associated with a hyperpolarizing shift of the "reluctant" component of activation. Norepinephrine inhibited wt and beta3-/- 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 beta3-/- 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.
authors.affiliation: Department of Life Science, Pohang University of Science and Technology, San-31, Hyoja-Dong, Pohang, 790-784, Republic of Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Namkung
authors.forename: S M
authors.initials: SM
authors.lastname: Smith
authors.forename: S B
authors.initials: SB
authors.lastname: Lee
authors.forename: N V
authors.initials: NV
authors.lastname: Skrypnyk
authors.forename: H L
authors.initials: HL
authors.lastname: Kim
authors.forename: H
authors.initials: H
authors.lastname: Chin
authors.forename: R H
authors.initials: RH
authors.lastname: Scheller
authors.forename: R W
authors.initials: RW
authors.lastname: Tsien
authors.forename: H S
authors.initials: HS
authors.lastname: Shin
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D011487:Protein Conformation; D009435:Synaptic Transmission
chemical_list: D015220:Calcium Channels; D009638:Norepinephrine