Disease relevance of Kcnma1

• Here, we demonstrate that the hypoxia sensitivity of BK channel alpha-subunits is splice-variant-specific [1].
• These results reveal a central role for BK channels in urinary bladder function and indicate that BK channel dysfunction leads to overactive bladder and urinary incontinence [2].
• Slo(-/-) mice did, however, show increased resistance to noise-induced hearing loss [3].
• Interestingly, carbachol stimulated BK channel activity but through a pertussis toxin (PTX)-sensitive pathway that was independent of L-type Ca2+ channel activity [4].
• Furthermore, 17beta-estradiol, which enhances the activity of the BK channel alpha-subunit only in the presence of the beta1-subunit, significantly increased flavoprotein oxidation in rat ventricle myocytes and decreased the rate of cell death under simulated ischemia [5].

Psychiatry related information on Kcnma1

• These results indicate that the BK channel has an important role in erectile function, and loss of the BK channel leads to erectile dysfunction [6].

High impact information on Kcnma1

• Here we show that targeted deletion of the gene for the beta1 subunit leads to a decrease in the calcium sensitivity of BK channels, a reduction in functional coupling of calcium sparks to BK channel activation, and increases in arterial tone and blood pressure [7].
• Complementary DNAs (cDNAs) from mSlo, a gene encoding calcium-activated potassium channels, were isolated from mouse brain and skeletal muscle, sequenced, and expressed in Xenopus oocytes [8].
• BK channel beta4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures [9].
• Our results indicate that NT-3 stimulates BK channel activity in cortical neurons through a signaling pathway that involves Trk tyrosine kinase, phospholipase C, and protein dephosphorylation and is calcium-dependent [10].
• During angiotensin II infusion, arterial smooth muscle BK channel function was decreased in wild type (WT) but not in NFATc3 null (NFATc3(-/-)) mice [11].

Biological context of Kcnma1

• Mouse Kcnma1 transcripts, 5' and 3' ESTs, and genomic sequences were examined for the utilization of alternative splicing in the mouse transcriptome [12].
• Here we demonstrated that alternative splicing at site of splicing C2 in the mouse BK channel C terminus generates five distinct splice variants: ZERO, e20, e21(STREX), e22, and a novel variant deltae23 [13].
• These results suggest that Slo channels comprise a multigene family, defined by a combination of sensitivity to voltage and a variety of intracellular factors [14].
• Thus alternative pre-mRNA splicing from a single site of splicing provides a mechanism to generate a physiologically diverse complement of BK channel alpha-subunits that differ dramatically in their tissue distribution, trafficking, and regulation [13].
• Mutagenesis of the central two LZ1 d position leucines to alanine in the BK channel also eliminated regulation by endogenous PKA in HEK293 cells without altering the channel sensitivity to activation by voltage or by exogenous purified PKA [15].

Anatomical context of Kcnma1

• Urinary bladder smooth muscle cells of Slo(-/-) mice lacked calcium- and voltage-activated BK currents, whereas local calcium transients ("calcium sparks") and voltage-dependent potassium currents were unaffected [2].
• To confirm the genetic identity of the maxi-K channel and to probe its specific roles, we studied parotid glands in mice with the K(Ca)1.1 gene ablated [16].
• The expression of Slo channels (alpha subunits of BK channels) was investigated in the developing mouse cochlea using a polyclonal antibody against the C-terminal part of the protein (residues 1098-1196) [17].
• The first BK channel immunoreactivity was observed in the cochlea at E18, where it was localized within the cytoplasm of cells lining the area of the organ of Corti and the spiral ganglion [17].
• 17beta-Estradiol upregulates distinct maxi-K channel transcripts in mouse uterus [18].

Associations of Kcnma1 with chemical compounds

• Thus LZ1 is required for the association and regulation of mammalian BK channels by PKA, and other putative leucine zippers in the BK channel protein may provide anchoring for other regulatory enzyme complexes [15].
• BK channels localize to the luminal membrane of crypt, and reverse transcription-PCR results confirm the expression of the BK channel alpha-subunit in isolated distal colonic crypts [19].
• Like Slo1 subunits responsible for the Ca(2+) and voltage-activated BK-type channel, the Slo3 alpha subunit contains a pore module with homology to voltage-gated K(+) channels and also an extensive cytosolic C terminus thought to be responsible for ligand dependence [20].
• Myometrial maxi-K channel beta1 subunit modulation during pregnancy and after 17beta-estradiol stimulation [21].
• We conclude that activation of calcineurin and NFATc3 during sustained angiotensin II signaling down-regulates the expression of the beta1 subunit of the BK channel, which in turn contributes to arterial dysfunction and the development of hypertension [11].

Regulatory relationships of Kcnma1

• These data suggest that IK1 channels inhibit maxi-K channel activity via a direct, membrane-delimited interaction between the channel proteins [22].

Other interactions of Kcnma1

• We demonstrate here a novel interaction between two types of Ca2+-activated K channels: maxi-K channels, encoded by the KCa1.1 gene, and IK1 channels (KCa3.1) [22].
• The kinetic behavior of Slo3 currents also differs markedly from Slo1 [20].
• Slo(-/-) mice were viable but exhibited moderate ataxia [2].
• In parallel, the specific BK channel blocker iberiotoxin abolished early glucocorticoid inhibition of corticotropin-releasing factor-stimulated ACTH secretion [23].
• An antibody against the 442 carboxy-terminal amino acids of the BK channel alpha-subunit detects high immunoreactivity within the telencephalon in cerebral cortices, olfactory bulb, basal ganglia and hippocampus, while lower levels are found in basal forebrain regions and amygdala [24].

Analytical, diagnostic and therapeutic context of Kcnma1

• RT-PCR analysis revealed the presence of two mSlo beta-subunits (Kcnmb1 and Kcnmb4) in parotid tissue [25].
• Immunoblotting demonstrates that the total maxi-K channel alpha subunit expression mimics transcript regulation [18].
• BK channel beta1-subunit regulation of calcium handling and constriction in tracheal smooth muscle [26].
• The ATP analog AMP-PNP has only minimal effects on channel activity after treatment with NS004, suggesting that hydrolysis of the ATP is required for its action on mSlo [27].
• Using patch-clamp recordings and immunofluorescence, we characterized BK channel expression in mouse inner hair cells [28].

References