Molecular Determinants of Intracellular pH Modulation of Human Kv1.4 N-Type Inactivation
2002; American Society for Pharmacology and Experimental Therapeutics; Volume: 62; Issue: 1 Linguagem: Inglês
10.1124/mol.62.1.127
ISSN1521-0111
AutoresBenzy J. Padanilam, Tong Lü, Toshinori Hoshi, Beena A. Padanilam, E F Shibata, Hon-Chi Lee,
Tópico(s)Blood disorders and treatments
ResumoA-type K + currents serve important functions in neural and cardiac physiology. The human A-type Kv1.4 channel (hKv1.4) shows fast N-type inactivation when expressed in Xenopus laevis oocytes. We found that intracellular pH (pH i ) regulated the macroscopic inactivation time constant (τ) and current amplitude (I peak ), producing a 2-fold change with each pH unit change in the physiologically relevant range of 8.0 to 6.0. These effects of pH i were completely abolished by a large deletion in the hKv1.4 N terminus. Site-directed mutagenesis identified a histidine (H16) in the inactivation ball domain as a critical H + titratable site mediating the pH effects on N-type inactivation between pH 7.0 and 9.0. Substituting this histidine with arginine not only accelerated the time course of macroscopic channel inactivation but also eliminated the H + effects on hKv1.4. In addition, a glutamic acid (E2) in the ball domain constitutes another H + titratable site that mediates the pH effects in the more acidic pH range of 5.0 to 7.0. These results suggest that N-type inactivation in hKv1.4 is regulated by pH i in the physiologic range through ionization of specific amino acid residues in the ball domain. Such pH i effects may represent an important fundamental mechanism for physiological regulation of excitable tissue function.
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