Ca+2-activated K+ channel subunit alpha-1; BK channel; BKCA alpha; Ca+2-activated K+ channel, subfamily M subunit alpha-1; K(VCA)alpha; KCa1.1; Maxi K channel; MaxiK; Slo-alpha; Slo1; Slowpoke homolog; Slo homolog; hSlo (KCNMA1, KCNMA, SLO)

Function

• K+ channel activated by both membrane depolarization or increase in cytosolic Ca+2 that mediates export of K+
• also activated by the concentration of cytosolic Mg+2
• activation dampens the excitatory events that elevate cytosolic Ca+2 concentration &/or depolarize the cell membrane, thus contributes to repolarization of the membrane potential
• role in regulating excitability, involving
  • contraction of smooth muscle
  • tuning of hair cells in the cochlea
  • transmitter release
  • innate immunity
• in smooth muscles, its activation by high level of Ca+2, caused by ryanodine receptors in the sarcoplasmic reticulum, regulates membrane potential
• in cochlea cells, its number & kinetic properties partly determine the characteristic frequency of each hair cell & thus helps to establish a tonotopic map
• kinetics of KCNMA1 channels are determined by
  • alternative splicing
  • phosphorylation status
  • combination with modulating beta subunits
• highly sensitive to both iberiotoxin (IbTx) & charybdotoxin (CTX)
• ethanol & carbon monoxide-bound heme increase channel activation
• heme inhibits channel activation
• phosphorylated (probable) by kinases such as PKA &/or PKG
• in smooth muscles, phosphorylation affects activity
• homotetramer; which constitutes the Ca+2-activated K+ channel
• interacts with beta subunits KCNMB1, KCNMB2, KCNMB3 & KCNMB4
• beta subunits are accessory, & modulate its activity

Structure

• the S0 segment is essential for the modulation by the accessory beta subunits KCNMB1, KCNMB2, KCNMB3 & KCNMB4
• the S4 segment, which is characterized by a series of positively charged amino acids at every third position, is part of the voltage-sensor
• the pore-forming domain (also referred as P region) is
  • imbedded into the membrane
  • forms the selectivity filter of the pore
  • contains the signature sequence of K+ channels that displays selectivity to K+
• the RCK N-terminal domain mediates the homotetramerization, thus promoting the assembly of monomers into functional K+ channel
• includes binding sites for Ca+2 & Mg+2 (putative)
• the Ca+2 bowl
  • constitutes one of the Ca+2 sensors
  • probably acts as a Ca+2-binding site
  • other Ca+2 sensors regions are required for activation of the channel
• the heme-binding motif
  • mediates inhibition of channel activation by heme
  • carbon monoxide-bound heme leads to increased channel activation
• belongs to the K+ channel family, Ca+2-
• activated (TC 1.A.1.3) subfamily, KCa1.1/KCNMA1 sub-subfamily
• contains 1 RCK N-terminal domain

Compartment

membrane

Alternative splicing

• named isoforms=7
• may be partially controlled by hormonal stress
• additional isoforms seem to exist

Expression

• widely expressed
• not expressed in myocytes

Pathology

• defects in KCNMA1 are the cause of generalized epilepsy & paroxysmal dyskinesia

Notes

• initially thought to contain 2 functionally distinct parts:
  • core channel (from the N-terminus to the S9 segment) that mediates the channel activity
  • cytoplasmic tail (from the S9 segment to the C-terminus) that mediates the Ca+2 sensing
• however, some integration of function since the core channel also contains binding sites for Ca+2 & Mg+2

More general terms

• transmembrane 7 protein
• K+ channel subfamily M
• glycoprotein
• phosphoprotein

Component of

• Ca+2-activated K+ channel

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=3778
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:3778
• OMIM: https://mirror.omim.org/entry/600150
• OMIM: https://mirror.omim.org/entry/609446
• UniProt: http://www.uniprot.org/uniprot/Q12791.html