Journal of Neurophysiology, Vol 73, Issue 5 1892-1899, Copyright © 1995 by APS

ARTICLES

Sodium channel inactivation is impaired in equine hyperkalemic periodic paralysis

S. C. Cannon, L. J. Hayward, J. Beech and R. H. Brown Jr
Department of Neurobiology, Harvard Medical School, Boston 02115, USA.

1. Equine hyperkalemic periodic paralysis (E-HPP) is a dominantly inherited disorder of muscle that causes recurrent episodes of stiffness (myotonia) and weakness in association with elevated serum K+. Affected horses carry a mutant allele of the skeletal muscle isoform of the Na channel alpha-subunit. To understand how this mutation may cause the disease phenotype, the functional defect in Na channel behavior was defined physiologically by recording unitary currents from cell-attached patches on normal and affected equine myotubes. 2. The presence of the mutation was confirmed in our cell line by restriction digest of polymerase chain reaction (PCR)-amplified genomic DNA. Myotubes from the affected horse were heterozygous for the point mutation that codes for a Phe to Leu substitution in S3 of domain IV. This assay provides a rapid technique to screen for the mutation in horses at risk. 3. The primary physiological defect in mutant Na channels was an impairment of inactivation. This defect was manifest as bursts of persistent activity during which the channel closed and reopened throughout a maintained depolarization. Disrupted inactivation slowed the decay of the ensemble-averaged current and produced an eightfold increase in the steady-state open probability measured at the end of a 40-ms pulse. This point mutation identifies a new region of the alpha subunit that is important for rapid inactivation of the channel. 4. The persistent Na current was produced by a distinct mode of gating. Failure of a mutant channel to inactivate was infrequent and occurred in groups of consecutive trials.(ABSTRACT TRUNCATED AT 250 WORDS)

This article has been cited by other articles:

				S. L. Venance, S. C. Cannon, D. Fialho, B. Fontaine, M. G. Hanna, L. J. Ptacek, M. Tristani-Firouzi, R. Tawil, R. C. Griggs, and the CINCH investigators The primary periodic paralyses: diagnosis, pathogenesis and treatment Brain, January 1, 2006; 129(1): 8 - 17. [Abstract] [Full Text] [PDF]

				T. P. Nguyen and R. Horn Movement and Crevices Around a Sodium Channel S3 Segment J. Gen. Physiol., August 26, 2002; 120(3): 419 - 436. [Abstract] [Full Text] [PDF]

				R. L. Ruff Effects of temperature on slow and fast inactivation of rat skeletal muscle Na+ channels Am J Physiol Cell Physiol, November 1, 1999; 277(5): C937 - C947. [Abstract] [Full Text] [PDF]

				F. Lehmann-Horn and K. Jurkat-Rott Voltage-Gated Ion Channels and Hereditary Disease Physiol Rev, October 1, 1999; 79(4): 1317 - 1372. [Abstract] [Full Text] [PDF]

				R. L. Sah, R. G. Tsushima, and P. H. Backx Effects of local anesthetics on Na+ channels containing the equine hyperkalemic periodic paralysis mutation Am J Physiol Cell Physiol, August 1, 1998; 275(2): C389 - C400. [Abstract] [Full Text] [PDF]

				D. H. Hall, G. Gu, J. Garcia-Anoveros, L. Gong, M. Chalfie, and M. Driscoll Neuropathology of Degenerative Cell Death in Caenorhabditis elegans J. Neurosci., February 1, 1997; 17(3): 1033 - 1045. [Abstract] [Full Text] [PDF]