Disease relevance of Kcnb1

• Hypoxia (PO(2)= approximately 30 mm Hg) reversibly inhibited Kv1.2 and Kv2.1 currents only at potentials more positive than 30 mV [1].
• These findings provide a basis for future studies of (post)transcriptional mechanism(s) down-regulating Kcnb1 expression in a variety of cardiomyopathies and point towards a possible involvement of Kcnb1 in pituitary cell excitability and secretory activity regulated by osmolarity [2].
• Here we show that a putative Kv2.1 antagonist (C-1) stimulates insulin secretion from MIN6 insulinoma cells in a glucose- and dose-dependent manner while blocking voltage-dependent outward K(+) currents [3].
• However, attenuation of Kv2.1-encoded currents in Kv1DN mice did not suppress the arrhythmias [4].

High impact information on Kcnb1

• Both Kv2.1 and Kv1.5 contribute to the initiation of HPV [5].
• 5 and Kv2.1 to PASMC electrophysiology and vascular tone [5].
• Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes [5].
• Kv2.1- channel subunits are found to interact with the Fyn SH2 domain [6].
• Among K+ channel isoforms, Kv2.1, minK, and Kv1.4 were readily detected in tumors and at 1 day in culture [7].

Biological context of Kcnb1

• 2. Whole-cell patch clamp demonstrated the presence of delayed rectifier K+ currents inhibited by tetraethylammonium (TEA) and 4-aminopyridine, with similar Kd values to that of Kv2.1, correlating delayed rectifier gene expression with the K+ currents [8].
• The protein levels of other Kv alpha subunits, Kv1.2 and Kv2.1, in contrast, are not affected by the expression of the Kv4.2W362F transgene [9].
• In summary, our data indicate that the spatially restrictive upregulation of Kv2.1-encoded currents underlies the increased dispersion of the repolarization observed in Kv1DN mice [10].
• Crossbreeding of Kv1DN mice with mice expressing a truncated Kv2.1 polypeptide (Kv2DN) eliminated I(K,slow2) [10].
• Currents generated by coexpression of Kv2.1 with Kv9.3 alpha subunits were reversibly inhibited by hypoxia in the voltage range of the resting membrane potential (E(M)) of PA VSMCs ( approximately 28% at -40 mV) [1].

Anatomical context of Kcnb1

• Co-injection of Kv2.1 and Kv10.1a or b mRNAs in Xenopus oocytes produced smaller currents that in the Kv2.1 injected oocytes and a moderate reduction of the inactivation rate without any appreciable change in recovery from inactivation or voltage dependence of activation or inactivation [11].
• NFATc3 regulates Kv2.1 expression in arterial smooth muscle [12].
• Luciferase activities of the longest promoter-reporter construct reflected the level of endogenous Kcnb1 mRNA in myoblast, smooth muscle, and pituitary cell lines [2].
• This occurs together with increased activity of delayed- rectifier, voltage-gated potassium (Kv) channels and with hyperphosphorylation of Kv1.5 and Kv2.1 Kv channel alpha-subunits in sciatic nerve tissue and in primary Schwann cells [13].
• Inhibition of Kv2.1 voltage-dependent K+ channels in pancreatic beta-cells enhances glucose-dependent insulin secretion [3].

Associations of Kcnb1 with chemical compounds

• We found that sustained administration of Ang II decreased Kv currents (IKv) by reducing the expression of Kv2.1 K+ channel subunits [12].
• In L-cells, 10 to 100 microM OPC-18790 reduced Kv1.4, Kv1.5 and Kv2.1 currents by <30%, whereas quinidine was a more potent blocker (EC50 < 10 microM) and the I(Kr)-specific blocker dofetilide was without effect [14].
• The insulinotropic effect of acute Kv2.1 inhibition resulted from enhanced membrane depolarization and augmented intracellular Ca(2+) responses to glucose [3].
• Depletion of cellular cholesterol alters the buoyancy of the Kv2.1 associated rafts and shifts the midpoint of Kv2.1 inactivation by nearly 40 mV without affecting peak current density or channel activation [15].
• 5. These results can be explained with a model based on an allosteric model of inactivation in Kv2.1 (Klemic, K.G., C.-C. Shieh, G.E. Kirsch, and S.W. Jones. 1998. Biophys. J. 74:1779-1789) in which an absence of the NH(2) terminus results in accelerated inactivation from closed states relative to full-length Kv1 [16].

Regulatory relationships of Kcnb1

• Thus, Kv1.5 encodes the 4-AP-sensitive component of I(K,slow) in the mouse ventricle and confers sensitivity to 4-AP-induced prolongation of APD and QTC: Compensatory upregulation of Kv2.1 may explain the phenotypic differences between SWAP mice and the previously described transgenic mice expressing a truncated dominant-negative Kv1.1 construct [17].

Other interactions of Kcnb1

• Similar to Kv4.3, expression of Kvbeta1, as well as Kv1.5 and Kv2.1, is similar in wild-type and Kv4.2(-/-) ventricles [18].
• The non-Shaker Kv2.1 channel did not assemble with Kv1.1 or Kv1 [19].
• In contrast, Kv1.2, Kv1.3, and Kv2.1 showed variable subcellular distribution depending upon cellular context [20].
• Substitution of linkers from the slowly activating Shab and Shaw channels resulted in a three-to fourfold slowing of activation and deactivation [21].
• We report here the initial characterization of 18 mutations in the S3-S4 linker of the Shaker channel, including deletions, insertions, charge change, substitution of prolines, and chimeras replacing the 25-residue Shaker linker with 7- or 9-residue sequences from Shab, Shaw, or Shal [21].

Analytical, diagnostic and therapeutic context of Kcnb1

• Reduced mRNA expression of O(2)-sensitive K(+) channels (Kv1.5 and Kv2.1) was shown by reverse transcriptase-polymerase chain reaction in the rat aorta [22].
• Northern blot analyses and real-time PCR revealed upregulation of Kv2.1 transcript in Kv1DN mice [10].
• Parallel immunofluorescence studies detected decreases in the expression of K+ channel subunit proteins, Kir2.1, Kir2.3, and Kv2.1 in MSNs, which contribute to the formation of the channel ionophores for these currents [23].
• The cloned human delayed rectifying K+ channel Kv2.1 (drk1) was expressed in clonal mouse fibroblasts (L-cells) and rat basophilic leukemia cells (RBL-1) by direct cytoplasmic microinjection of complementary RNA (cRNA) [24].

References