Disease relevance of Kcna3

• Interestingly, although Kv1.3-/- mice on the high-calorie diet gain weight, they remain euglycemic, with low blood insulin levels [1].
• The voltage-gated potassium channel Kv1.3 regulates energy homeostasis and body weight [2].
• Kv1.3 and Kir2.1 expression was impaired in brain during cancer cachexia [3].
• T lymphocytes with unusually high expression of the voltage-gated Kv1.3 channel (Kv1.3(high) cells) have been implicated in the pathogenesis of experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis [4].
• Immunogold labeling and electron microscopy showed that the distribution of FLAG epitope-tagged Kv1.3 channels (Kv1.3/FLAG) significantly differs from the stochastic Poisson distribution in the plasma membrane of human T lymphoma cells [5].

High impact information on Kcna3

• A family of three closely related potassium channel genes (MK1, MK2, and MK3) that are encoded at distinct genomic loci has been isolated [6].
• The murine gamma-herpesvirus-68 MK3 protein inhibits CD8(+) T cell recognition by ubiquitinating the cytoplasmic tails of classical MHC class I heavy chains [7].
• However, TAP degradation also broadened the MK3 inhibitory repertoire and achieved a remarkable resistance to MHC class I upregulation by interferon-gamma, suggesting that it represents a specific adaptation to immune evasion in lymphoid tissue [7].
• In accordance with this heightened sense of smell, Kv1.3-/- mice have glomeruli or olfactory coding units that are smaller and more numerous than those of wild-type mice [8].
• Inhibition of Kv1.3 activity facilitates the translocation of the glucose transporter, GLUT4, to the plasma membrane [1].

Chemical compound and disease context of Kcna3

• The 5-HT-mediated suppression of Kv1.3 currents proceeds via activation of a pertussis toxin-sensitive G protein and a subsequent rise in intracellular Ca2+, but Ca2+ does not directly block the channel [9].

Biological context of Kcna3

• These data suggest that Kv1.3 plays a far more reaching role in signal transduction, development, and olfactory coding than that of the classically defined role of a potassium channel-to shape excitability by influencing membrane potential [8].
• Potassium currents in olfactory bulb mitral cells from Kv1.3 null mice have slow inactivation kinetics, a modified voltage dependence, and a dampened C-type inactivation and fail to be modulated by activators of receptor tyrosine signaling cascades [8].
• These results pinpoint a pathway through which K channels regulate peripheral glucose homeostasis, and identify Kv1.3 as a pharmacologic target for the treatment of diabetes [1].
• Gene inactivation causes mice (Kv1.3-/-) exposed to a high-fat diet to gain less weight and be less obese than littermate control [1].
• Here we show that Kv1.3 gene deletion and channel inhibition increase peripheral insulin sensitivity in vivo [1].

Anatomical context of Kcna3

• We conclude that Kv1.3 inhibition improves insulin sensitivity by increasing the amount of GLUT4 at the plasma membrane [1].
• Kv1.3 is a voltage-gated potassium (K) channel expressed in a number of tissues, including fat and skeletal muscle [1].
• Kv1.3 channels are expressed in several tissues and believed to participate in cell volume regulation, apoptosis, T cell activation and renal solute homeostasis [2].
• 3. Immunohistochemical localization showed each channel to have a unique subcellular distribution: Kv1.1 immunoreactivity was detected in the dendrites and axons terminal, whereas Kv1.2 and Kv1.3 subunits were localized to the axon and the postsynaptic membrane of the rod ribbon synapse, respectively [10].
• Functional Kv1.3 expression levels increased substantially in a myelin-specific rat T cell line following myelin antigen stimulation, peaking at 15-20 h and then declining to baseline over the next 7 days, in parallel with the acquisition and loss of encephalitogenicity [4].

Associations of Kcna3 with chemical compounds

• Removal of K+o had a similar effect on current through Kv1.3 when the histidine at the homologous position (H404) was protonated (pH 6.0) [11].
• Angiotensin II (AngII) upregulated Pax-2 protein and Pax-2 mRNA expression via the AngII type 2 (AT(2)) receptor in MK4 but not in MK3 cells [12].
• We characterized the action of verapamil and N-methyl-verapamil on current through the delayed-rectifier potassium channel Kv1.3 mouse (mKv1.3) [13].
• The two T-cell K+ channels, Kv3.1 and Kv1.3, with widely divergent pore properties, differ by a single residue in this internal P-region, leucine 401 in Kv3.1 corresponding to valine 398 in Kv1 [14].
• Ceramide inhibited Kv1.3 potassium channels, store operated Ca2+ -entry (SOC) and depolarized the plasma membrane to which contribution of spontaneously formed ceramide channels is possible [15].

Regulatory relationships of Kcna3

• However, LPS treatment induced Kv1.3 and downregulated Kir2.1 expression, and TNF-alpha administration mimicked these results [3].
• Upregulation of Kv1.3 K(+) channels in microglia deactivated by TGF-beta [16].

Other interactions of Kcna3

• While Kv1.3 was further induced, Kir2.1 was down-regulated [17].
• MTX-HsTx1 displays the activity of MTX on SK channel, whereas it exhibits the pharmacological profile of HsTx1 on Kv1.1, Kv1.2, Kv1.3, and IK channels [18].
• Here we report that KChAP is a chaperone for Kv1.3 and Kv4 [19].
• In accordance with the observed changes in DR current density, the mRNA level for Kv1.3 (assessed by competitive RT-PCR) increased fivefold after treatment of microglia with TGF-beta [16].
• Pharmacological characterization of the pneumococcal cell wall- and lipopolysaccharide-induced currents with specific ion channel blockers indicated for both cases expression of the charybdotoxin/margatoxin-sensitive Kv1.3 subtype of the Shaker family of voltage-dependent potassium channels [20].
• Taken together, our results demonstrate that Kv1.5 co-associates with Kv1.3, generating functional heterotetramers in macrophages [21].

Analytical, diagnostic and therapeutic context of Kcna3

• While food intake did not differ significantly between Kv1.3(-/-) and controls, basal metabolic rate, measured at rest by indirect calorimetry, was significantly higher in knockout animals [2].
• Examination of Kv1.3-deficient mice (Kv1.3(-/-)), generated by gene targeting, revealed a previously unrecognized role for Kv1.3 in body weight regulation [2].
• In flow cytometry experiments, ShK-F6CA specifically stained Kv1.3-expressing cells with a detection limit of approximately 600 channels per cell [4].
• Dendrotoxin (DTX) and charybdotoxin (CTX), antagonists of Kv1.1 and Kv1.3 channels, respectively, decreased thymocyte yields in organ culture without affecting thymocyte viability [22].
• 1. We investigated the action of TsTX-Kalpha on cloned Kv1.3 channels of the Shaker subfamily of voltage-gated potassium channels, using the voltage-clamp technique [23].

References