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The KV4 Channel Subfamily (Shal)

By Alon Meir, Ph.D.

The KV4 subfamily of voltage dependent K+ channels is the mammalian parallel of the Drosophila Shal K+ channel. These currents have “A-type” namely transient profile, which is characterized by fast activation followed by fast inactivation, upon depolarization of the membrane potential. Both the KV1 and the KV4 families generate “A-type” currents, with the latter activating at lower voltage1,2.

There are three members in this subfamily designated KV4.1-3. Alternative splicing of KV4.3 creates three variant products, further contributing to the divergence of the subfamily2. Members of the KV4 subfamily are expressed in heart3, neurons4 and some smooth muscle such as the uterus, where estrogen down regulates KV4.3 channels (which is correlated to their down regulation with pregnancy propagation)5. In the heart KV4.2 and KV4.3 channels underlie part of Ito, with differential expression in different parts of the heart and across species3. In neurons, KV4 channels are correlated with the sub-threshold transient K+ currents4. In the substantia nigra, dopaminargic neurons express KV4.3, which play a key role in the control of an intrinsic pacemaker activity6.

KV4 channels were shown to interact with auxiliary β subunits (KVβ1 and 2), via a C-terminal interaction, which increase their membrane expression leading to larger current density7. Interestingly, KVβ1.2 confers O2 sensitivity to KV4.2 channels, which suggests a role in response to hypoxia8.

Recently, many reports show that KV4 channels interact with, and their properties are modulated by, K+ Channel Interacting Proteins (KChIP), such as CALP and DREAM. In general, KChIP increases membrane expression, slows the inactivation and enhances recovery from inactivation of KV4 channels6, 9-11. KV4.2 channels were also shown to interact with PSD9512 and frequenin13.

Phosphorylation also plays a major role in KV4 channel function and modulation, as the KV4.2 sequence contains consensus sites for ERK/MAPK, PKA, PKC and CaMKII14. These channels were shown to be phosphorylated by PKA15.

A specific and potent blocker of this subfamily, Phrixotoxin-2 (#STP-710), was found within the venom of the tarantula (see below)16.

References

  1. Hille, B. (2001) Ion Channels of excitable membranes. 3rd edition.
  2. Coetzee, W. A. et al. (1999) Anals N. Y. Acad. Sci. 868, 233.
  3. Brahmajothi, M. V. et al. (1999) J. Gen. Physiol. 113, 581.
  4. Seodio, P. and Rudy, B. (1998) J. Neurophysiol. 79, 1081.
  5. Song, M. et al. (2001) J. Biol. Chem. 276, 31883.
  6. Liss, B. et al. (2001) EMBO J. 20, 5715.
  7. Yang, E. K. et al. (2001) J. Biol. Chem. 276, 4839.
  8. Perez-Garcia, M. T. et al. (1999) J. Gen. Physiol. 113, 897.
  9. Bahring, R. et al. (2001) J. Biol. Chem. 276, 23888.
  10. Holmqvist, M. H. et al. (2002) P.N.A.S. USA 99, 1035.
  11. Morohashi, Y. et al. (2002) J. Biol. Chem. 277, 14965.
  12. Wong, W. et al. (2002) J. Biol. Chem. In press 10.1074/jbc.M109412200.
  13. Nakamura, T. Y. et al. (2001) P.N.A.S. USA 98, 12808.
  14. Varga, A. W. et al. (2000) Learn. Mem. 7, 321.
  15. Anderson, A. E. et al. (2000) J. Biol. Chem. 275, 5337.
  16. Diochot, S. et al. (1999) Br. J. of Pharmacol. 126, 251.