TY - JOUR
T1 - 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
AU - Namkung, Yoon
AU - Smith, Stephen M.
AU - Lee, Seong Beom
AU - Skrypnyk, Nataliya V.
AU - Kim, Hyung Lae
AU - Chin, Hemin
AU - Scheller, Richard H.
AU - Tsien, Richard W.
AU - Shin, Hee Sup
PY - 1998/9/29
Y1 - 1998/9/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0032578356&partnerID=8YFLogxK
U2 - 10.1073/pnas.95.20.12010
DO - 10.1073/pnas.95.20.12010
M3 - Article
C2 - 9751781
AN - SCOPUS:0032578356
SN - 0027-8424
VL - 95
SP - 12010
EP - 12015
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -