Modulation of A-type potassium channels by stress mediators

Yang, Kefan GND

A-type voltage-gated potassium (Kv) channels open on membrane depolarization and undergo subsequent rapid inactivation with importance in fine-tuning of cellular excitability. To serve diverse cellular needs, the inactivation is regulated by numerous mechanisms; for example, cysteine residues in the N-terminal inactivation ball domain make the inactivation susceptible to redox state changes. Hydrogen sulfide (H2S), which is enzymatically generated in various tissues, is increasingly recognized as an important signaling molecule, particularly in the cardiovascular and nervous systems. In aqueous solutions, H2S is in equilibrium with more oxidized sulfur species, e.g., polysulfides, and these sulfur-containing compounds are often collectively termed reactive sulfur species (RSS). Various roles of RSS have been identified, such as regulation of neuronal excitability, but often the mechanisms are not well understood. In this work, the H2S donor NaHS and the polysulfide donors Na2Sn were used to study whether and how A-type Kv channels might be regulated by RSS. Using the patch-clamp method, we found that Na2Sn broaden single action potentials in murine dorsal root ganglion neurons and slow the inactivation of their natively expressed A-type Kv channels (e.g., Kv1.4, Kv3.4). Therefore, we studied the functional properties of recombinant Kv1.4 and Kv3.4 and mutants thereof upon heterologous expression in HEK293T cells. Polysulfides (Na2Sn) were > 1000 times more effective than NaHS in slowing down inactivation with the potency increasing with the number of sulfur atoms (Na2S2 < Na2S3 < Na2S4), indicating that spontaneously formed Na2Sn in NaHS solutions were the active components. A cysteine residue at position 13 (C13) in the ball domain of Kv1.4, and C6, C24 in that of Kv3.4 mediated the slowing of inactivation by RSS.

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