KCNA4 explained

Symbol:	K_channel_TID
Potassium channel Kv1.4 tandem inactivation domain
Pfam:	PF07941
Interpro:	IPR012897
Scop:	1kn7

Potassium voltage-gated channel subfamily A member 4 also known as K_v1.4 is a protein that in humans is encoded by the KCNA4 gene.^{[1] [2] [3]} It contributes to the cardiac transient outward potassium current (I_to1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.^[4]

Description

Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the A-type potassium current class, the members of which may be important in the regulation of the fast repolarizing phase of action potentials in heart and thus may influence the duration of cardiac action potential. The coding region of this gene is intronless, and the gene is clustered with genes KCNA3 and KCNA10 on chromosome 1 in humans.^[3]

KCNA4 (Kv1.4) contains a tandem inactivation domain at the N terminus. It is composed of two subdomains. Inactivation domain 1 (ID1, residues 1-38) consists of a flexible N terminus anchored at a 5-turn helix, and is thought to work by occluding the ion pathway, as is the case with a classical ball domain. Inactivation domain 2 (ID2, residues 40-50) is a 2.5 turn helix with a high proportion of hydrophobic residues that probably serves to attach ID1 to the cytoplasmic face of the channel. In this way, it can promote rapid access of ID1 to the receptor site in the open channel. ID1 and ID2 function together to bring about fast inactivation of the Kv1.4 channel, which is important for the role of the channel in short-term plasticity.^[5]

Interactions

KCNA4 has been shown to interact with DLG4,^{[6] [7] [8] [9]} KCNA2^[10] and DLG1.^{[6] [8] [11]}

See also

• Voltage-gated potassium channel
• Voltage-gated potassium-channel Kv1.4 IRES

Further reading

• Scott HS, Litjens T, Hopwood JJ, Morris CP . PCR detection of two RFLPs in exon I of the alpha-L-iduronidase (IDUA) gene . Human Genetics . 90 . 3 . 327 . November 1992 . 1362562 . 10.1007/bf00220095 . 22700269 .
• Gessler M, Grupe A, Grzeschik KH, Pongs O . The potassium channel gene HK1 maps to human chromosome 11p14.1, close to the FSHB gene . Human Genetics . 90 . 3 . 319–21 . November 1992 . 1487251 . 10.1007/bf00220091 . 10237322 .
• Philipson LH, Hice RE, Schaefer K, LaMendola J, Bell GI, Nelson DJ, Steiner DF . Sequence and functional expression in Xenopus oocytes of a human insulinoma and islet potassium channel . Proceedings of the National Academy of Sciences of the United States of America . 88 . 1 . 53–7 . January 1991 . 1986382 . 50746 . 10.1073/pnas.88.1.53 . 1991PNAS...88...53P . free .
• Tamkun MM, Knoth KM, Walbridge JA, Kroemer H, Roden DM, Glover DM . Molecular cloning and characterization of two voltage-gated K+ channel cDNAs from human ventricle . FASEB Journal . 5 . 3 . 331–7 . March 1991 . 2001794 . 10.1096/fasebj.5.3.2001794 . free . 23737559 .
• Kim E, Niethammer M, Rothschild A, Jan YN, Sheng M . Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases . Nature . 378 . 6552 . 85–8 . November 1995 . 7477295 . 10.1038/378085a0 . 1995Natur.378...85K . 4362906 .
• Klocke R, Roberds SL, Tamkun MM, Gronemeier M, Augustin A, Albrecht B, Pongs O, Jockusch H . 6 . Chromosomal mapping in the mouse of eight K(+)-channel genes representing the four Shaker-like subfamilies Shaker, Shab, Shaw, and Shal . Genomics . 18 . 3 . 568–74 . December 1993 . 7905852 . 10.1016/S0888-7543(05)80358-1 .
• Philipson LH, Eddy RL, Shows TB, Bell GI . Assignment of human potassium channel gene KCNA4 (Kv1.4, PCN2) to chromosome 11q13.4→q14.1 . Genomics . 15 . 2 . 463–4 . February 1993 . 8449523 . 10.1006/geno.1993.1094 .
• Niethammer M, Kim E, Sheng M . Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases . The Journal of Neuroscience . 16 . 7 . 2157–63 . April 1996 . 8601796 . 6578538 . 10.1523/JNEUROSCI.16-07-02157.1996 .
• Kim E, Sheng M . Differential K+ channel clustering activity of PSD-95 and SAP97, two related membrane-associated putative guanylate kinases . Neuropharmacology . 35 . 7 . 993–1000 . 1997 . 8938729 . 10.1016/0028-3908(96)00093-7 . 23755452 .
• Kim E, Naisbitt S, Hsueh YP, Rao A, Rothschild A, Craig AM, Sheng M . GKAP, a novel synaptic protein that interacts with the guanylate kinase-like domain of the PSD-95/SAP90 family of channel clustering molecules . The Journal of Cell Biology . 136 . 3 . 669–78 . February 1997 . 9024696 . 2134290 . 10.1083/jcb.136.3.669 .
• Niethammer M, Valtschanoff JG, Kapoor TM, Allison DW, Weinberg RJ, Craig AM, Sheng M . CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90 . Neuron . 20 . 4 . 693–707 . April 1998 . 9581762 . 10.1016/S0896-6273(00)81009-0 . 16068361 . free .
• Brenman JE, Topinka JR, Cooper EC, McGee AW, Rosen J, Milroy T, Ralston HJ, Bredt DS . 6 . Localization of postsynaptic density-93 to dendritic microtubules and interaction with microtubule-associated protein 1A . The Journal of Neuroscience . 18 . 21 . 8805–13 . November 1998 . 9786987 . 6793550 . 10.1523/JNEUROSCI.18-21-08805.1998 .
• Coleman SK, Newcombe J, Pryke J, Dolly JO . Subunit composition of Kv1 channels in human CNS . Journal of Neurochemistry . 73 . 2 . 849–58 . August 1999 . 10428084 . 10.1046/j.1471-4159.1999.0730849.x . 20632070 . free .
• D'Adamo MC, Imbrici P, Sponcichetti F, Pessia M . Mutations in the KCNA1 gene associated with episodic ataxia type-1 syndrome impair heteromeric voltage-gated K(+) channel function . FASEB Journal . 13 . 11 . 1335–45 . August 1999 . 10428758 . 10.1096/fasebj.13.11.1335 . 12876970 . free .
• Hogan A, Shepherd L, Chabot J, Quenneville S, Prescott SM, Topham MK, Gee SH . Interaction of gamma 1-syntrophin with diacylglycerol kinase-zeta. Regulation of nuclear localization by PDZ interactions . The Journal of Biological Chemistry . 276 . 28 . 26526–33 . July 2001 . 11352924 . 10.1074/jbc.M104156200 . free .
• Cukovic D, Lu GW, Wible B, Steele DF, Fedida D . A discrete amino terminal domain of Kv1.5 and Kv1.4 potassium channels interacts with the spectrin repeats of alpha-actinin-2 . FEBS Letters . 498 . 1 . 87–92 . June 2001 . 11389904 . 10.1016/S0014-5793(01)02505-4 . 20622483 . free . 2001FEBSL.498...87C .
• Imamura F, Maeda S, Doi T, Fujiyoshi Y . Ligand binding of the second PDZ domain regulates clustering of PSD-95 with the Kv1.4 potassium channel . The Journal of Biological Chemistry . 277 . 5 . 3640–6 . February 2002 . 11723117 . 10.1074/jbc.M106940200 . free .
• Piserchio A, Pellegrini M, Mehta S, Blackman SM, Garcia EP, Marshall J, Mierke DF . The PDZ1 domain of SAP90. Characterization of structure and binding . The Journal of Biological Chemistry . 277 . 9 . 6967–73 . March 2002 . 11744724 . 10.1074/jbc.M109453200 . free .

Notes and References

1. Philipson LH, Schaefer K, LaMendola J, Bell GI, Steiner DF . Sequence of a human fetal skeletal muscle potassium channel cDNA related to RCK4 . Nucleic Acids Research . 18 . 23 . 7160 . December 1990 . 2263489 . 332806 . 10.1093/nar/18.23.7160 .
2. Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA, Robertson GA, Rudy B, Sanguinetti MC, Stühmer W, Wang X . 6 . International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels . Pharmacological Reviews . 57 . 4 . 473–508 . December 2005 . 16382104 . 10.1124/pr.57.4.10 . 219195192 .
3. Web site: Entrez Gene: KCNA4 potassium voltage-gated channel, shaker-related subfamily, member 4.
4. Oudit GY, Kassiri Z, Sah R, Ramirez RJ, Zobel C, Backx PH . The molecular physiology of the cardiac transient outward potassium current (I(to)) in normal and diseased myocardium . Journal of Molecular and Cellular Cardiology . 33 . 5 . 851–72 . May 2001 . 11343410 . 10.1006/jmcc.2001.1376 . 829154 .
5. Wissmann R, Bildl W, Oliver D, Beyermann M, Kalbitzer HR, Bentrop D, Fakler B . Solution structure and function of the "tandem inactivation domain" of the neuronal A-type potassium channel Kv1.4 . The Journal of Biological Chemistry . 278 . 18 . 16142–50 . May 2003 . 12590144 . 10.1074/jbc.M210191200 . free .
6. Inanobe A, Fujita A, Ito M, Tomoike H, Inageda K, Kurachi Y . Inward rectifier K+ channel Kir2.3 is localized at the postsynaptic membrane of excitatory synapses . American Journal of Physiology. Cell Physiology . 282 . 6 . C1396-403 . June 2002 . 11997254 . 10.1152/ajpcell.00615.2001 .
7. Niethammer M, Valtschanoff JG, Kapoor TM, Allison DW, Weinberg RJ, Craig AM, Sheng M . CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90 . Neuron . 20 . 4 . 693–707 . April 1998 . 9581762 . 10.1016/S0896-6273(00)81009-0 . 16068361 . free .
8. Kim E, Sheng M . Differential K+ channel clustering activity of PSD-95 and SAP97, two related membrane-associated putative guanylate kinases . Neuropharmacology . 35 . 7 . 993–1000 . 1996 . 8938729 . 10.1016/0028-3908(96)00093-7 . 23755452 .
9. Eldstrom J, Doerksen KW, Steele DF, Fedida D . N-terminal PDZ-binding domain in Kv1 potassium channels . FEBS Letters . 531 . 3 . 529–37 . November 2002 . 12435606 . 10.1016/S0014-5793(02)03572-X . 40689829 . free . 2002FEBSL.531..529E .
10. Coleman SK, Newcombe J, Pryke J, Dolly JO . Subunit composition of Kv1 channels in human CNS . Journal of Neurochemistry . 73 . 2 . 849–58 . August 1999 . 10428084 . 10.1046/j.1471-4159.1999.0730849.x . 20632070 . free .
11. Eldstrom J, Choi WS, Steele DF, Fedida D . SAP97 increases Kv1.5 currents through an indirect N-terminal mechanism . FEBS Letters . 547 . 1–3 . 205–11 . July 2003 . 12860415 . 10.1016/S0014-5793(03)00668-9 . 34857270 . free . 2003FEBSL.547..205E .