Variants of the KCNMB3 regulatory subunit of maxi BK channels affect channel inactivation.
The steady-state and kinetic properties of the KCNMB3 regulatory subunits associated with calcium-activated potassium channels (BK channels) are presented. BK channels containing four sequence variants (V1-V4) in the four different isoforms of the beta-subunit (beta3a, beta3b, beta3c, and beta3d) were expressed in Xenopus oocytes. Reconstituted BK channel inactivation ranged from none to around 90% inactivation. In particular, channels expressing the beta3b-V4 variant displayed a right shift in the potassium current voltage-dependence of activation and inactivated to about 30% of the maximum conductance, compared with wild-type beta3b channels that showed no inactivation. When the membrane potential was depolarized, BK channels inactivated with a very rapid time course (approximately 2-6 ms). This same variant was previously demonstrated to show subtly higher incidence in patients with idiopathic epilepsy (IE) compared with controls, especially when combined with variant V2 (combined heterozygotes). Furthermore, the gene maps to a region containing a susceptibility factor for this disorder. Taken together, these data suggest that neurons expressing BK channels composed of the beta3b-V4 variant subunit may experience reduced levels of inhibition and may therefore play permissive roles in high levels of neuronal activity that is characteristic of epilepsy.
Hu
Song
S
Department of Biological Sciences, University of Alberta, Edmonton, Alberta T6G 2E9, Canada.
Labuda
Malgorzata Z
MZ
Pandolfo
Massimo
M
Goss
Greg G
GG
McDermid
Heather E
HE
Ali
Declan W
DW
D000595:Amino Acid Sequence; D000818:Animals; D004594:Electrophysiology / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D014644:Genetic Variation; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D009865:Oocytes / Q000737:chemistry / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000502:physiology; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D014982:Xenopus laevis
C403242:KCNMB3 protein, human; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D020033:Protein Isoforms; D021122:Protein Subunits; D012333:RNA, Messenger; D011188:Potassium