Disease relevance of Kcnma1

• We found that in hypertension, expression of the beta1 subunit was decreased relative to the pore-forming alpha subunit of the BK channel [1].
• The authors evaluated the effects of postinjury systemic administration of the maxi-K channel opener, BMS-204352, on behavioral and histologic outcome after lateral fluid percussion (FP) traumatic brain injury (TBI) in the rat [2].
• The maxi-K channel opener BMS-204352 attenuates regional cerebral edema and neurologic motor impairment after experimental brain injury [2].
• Involvement of BKCa alpha subunit tyrosine phosphorylation in vascular hyporesponsiveness of superior mesenteric artery following hemorrhagic shock in rats [3].
• The BK channel opener, NS1619, turned out to be gliotoxic, and this effect was not counteracted by paxilline and iberiotoxin.Our data show that blockade of BK channels aggravates OGD-induced cell damage and suggest that BK channels act as a kind of 'emergency brake' during and/or after ischemia [4].

Psychiatry related information on Kcnma1

• 4-Aryl-3-(hydroxyalkyl)quinolin-2-ones: novel maxi-K channel opening relaxants of corporal smooth muscle targeted for erectile dysfunction [5].

High impact information on Kcnma1

• Our results indicate instead that somatostatin stimulates BK channel activity through protein dephosphorylation [6].
• Thus, the hormonal stress axis is likely to control the excitable properties of epinephrine-secreting cells by regulating alternative splicing of Slo messenger RNA [7].
• These results support the novel concept that changes in BK channel subunit composition regulate arterial smooth muscle function [1].
• We conclude that downregulation of the beta1 subunit of the BK channel contributes to vascular dysfunction in hypertension [1].
• Ethanol inhibition of BK transients was caused by a reduction in Ca(2+) spark frequency (-49%), a subsarcolemmal Ca(2+) signal that evokes the BK transients, and a direct inhibition of BK channel steady-state activity (-44%) [8].

Chemical compound and disease context of Kcnma1

• A new study demonstrates that angiotensin-induced hypertension results in a marked decrease in expression of the beta subunit of the BK channel, suggesting a role for this critical subunit in the regulation of vascular tone [9].
• Upregulation of the BK channel alpha subunit contributes to the enhanced depressor response caused by tempol in DOCA-salt hypertension [10].

Biological context of Kcnma1

• Moreover, they reveal down-regulation by splice variants as a new mechanism that may contribute to the diverse levels of MaxiK channel expression in non-excitable and excitable cells [11].
• STREX alternative-exon adds to Slo channel a phosphorylation sequence that can invert protein kinase A (PKA) regulation from excitatory to inhibitory [12].
• This study pinpoints the Ca(2+) spark/BK channel negative-feedback mechanism as the primary effector of ethanol vasoconstriction [8].
• The expression pattern of Slo is consistent with its targeting into a presynaptic compartment, which implies an important role in neural transmission [13].
• BK channel activation and vasorelaxation by iloprost were similar in lean and ZDF rats [14].

Anatomical context of Kcnma1

• We hypothesize that Slo splicing in adrenal chromaffin cells in vivo is differentially regulated by the integrative, concentration- and time-dependent actions of glucocorticoids and androgens, with potentially important ramifications for stress-evoked catecholamine secretion [15].
• We identified a novel MaxiK alpha subunit splice variant (SV1) from rat myometrium that is also present in brain [11].
• Expression of Ca2+-activated BK channel mRNA and its splice variants in the rat cochlea [16].
• Extensive splicing of BK channel transcripts, however, does not seem to be used in mammalian hair cells as is done in lower vertebrates [16].
• Thus, we report (i) steroidal regulation of Slo splicing in the pituitary and (ii) participation of the male gonads in this regulation [17].

Associations of Kcnma1 with chemical compounds

• Alternative splicing of Slo channel gene programmed by estrogen, progesterone and pregnancy [12].
• Regulation of Slo potassium channel alternative splicing in the pituitary by gonadal testosterone [17].
• We conclude that PGI2 is the major AA metabolite in lean coronaries, and AA-mediated BK channel activation is impaired in ZDF coronaries due to reduced PGIS activity [14].
• Furthermore, a beta-subunit-dependent Slo channel activator, dehydrosoyasaponin I, was without effect on chromaffin cell BK current [18].
• A novel conotoxin from Conus betulinus, kappa-BtX, unique in cysteine pattern and in function as a specific BK channel modulator [19].

Regulatory relationships of Kcnma1

• In contrast, stimulation of P2Y2 receptors led to a 20% inhibition of co-expressed BK channel activity, a response that was sensitive to TEA [20].

Other interactions of Kcnma1

• Here we show that BK channel activation by leptin is dependent on the actin cytoskeleton, as it is prevented by actin filament stabilization and mimicked by actin disruption [21].
• Immunoblots showed a 73% reduction in PGI2 synthase (PGIS) expression in ZDF vessels compared with lean vessels, and there was no change in cyclooxygenase (COX) and BK channel expressions [14].
• Adenylate cyclase 5 and KCa1.1 channel are required for EGFR up-regulation of PCNA in native contractile rat basilar artery smooth muscle [22].
• Exogenous arachidonic acid (1-20 muM) stimulated BK channel activity through protein dephosphorylation as effectively as somatostatin and was also blocked by inhibitors of lipoxygenases but not by inhibitors of phospholipase A2 [23].
• These findings suggest that activation of mGluR by Homer-1a produced IP(3), which caused inositol-induced calcium release and a consequent BK channel opening, thus hyperpolarizing the injected neurons [24].

Analytical, diagnostic and therapeutic context of Kcnma1

• Hypophysectomy triggered an abrupt decrease in the proportion of Slo transcripts containing a "STREX" exon [7].
• The distribution of Slo protein was confirmed in microdissected brain areas by Western blotting and radioligand-binding studies [13].
• Tissue expression and distribution of the high-conductance Ca(2+)-activated K+ channel Slo was investigated in rat brain by immunocytochemistry, in situ hybridization, and radioligand binding using the novel high-affinity (Kd 22 pM) ligand [3H]iberiotoxin-D19C ([3H]IbTX-D19C), which is an analog of the selective maxi-K peptidyl blocker IbTX [13].
• In situ hybridization indicated high levels of Slo mRNA in the neocortex, olfactory system, habenula, striatum, granule and pyramidal cell layer of the hippocampus, and Purkinje cells [13].
• PCR screening of chromaffin cell RNA failed to reveal a homolog of an accessory beta subunit known to influence Slo channel function [18].

References