title: Acid-sensing ion channels interact with and inhibit BK K+ channels.
abstract: Acid-sensing ion channels (ASICs) are neuronal non-voltage-gated cation channels that are activated when extracellular pH falls. They contribute to sensory function and nociception in the peripheral nervous system, and in the brain they contribute to synaptic plasticity and fear responses. Some of the physiologic consequences of disrupting ASIC genes in mice suggested that ASIC channels might modulate neuronal function by mechanisms in addition to their H(+)-evoked opening. Within ASIC channel's large extracellular domain, we identified sequence resembling that in scorpion toxins that inhibit K(+) channels. Therefore, we tested the hypothesis that ASIC channels might inhibit K(+) channel function by coexpressing ASIC1a and the high-conductance Ca(2+)- and voltage-activated K(+) (BK) channel. We found that ASIC1a associated with BK channels and inhibited their current. Reducing extracellular pH disrupted the association and relieved the inhibition. BK channels, in turn, altered the kinetics of ASIC1a current. In addition to BK, ASIC1a inhibited voltage-gated Kv1.3 channels. Other ASIC channels also inhibited BK, although acidosis-dependent relief of inhibition varied. These results reveal a mechanism of ion channel interaction and reciprocal regulation. Finding that a reduced pH activated ASIC1a and relieved BK inhibition suggests that extracellular protons may enhance the activity of channels with opposing effects on membrane voltage. The wide and varied expression patterns of ASICs, BK, and related K(+) channels suggest broad opportunities for this signaling system to alter neuronal function.
authors.affiliation: Departments of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Elena Yermolaieva
authors.initials: EY
authors.lastname: Petroff
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Price
authors.forename: Vladislav
authors.initials: V
authors.lastname: Snitsarev
authors.forename: Huiyu
authors.initials: H
authors.lastname: Gong
authors.forename: Victoria
authors.initials: V
authors.lastname: Korovkina
authors.forename: Francois M
authors.initials: FM
authors.lastname: Abboud
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
mesh_terms: D062565:Acid Sensing Ion Channels; D000595:Amino Acid Sequence; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D004594:Electrophysiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D012604:Scorpion Venoms / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*
chemical_list: C568266:ASIC1 protein, human; C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D018076:DNA, Complementary; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012604:Scorpion Venoms; D015222:Sodium Channels