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CELLULAR AND MOLECULAR

Inhibition of the A-Type K⁺ Channels of Dorsal Root Ganglion Neurons by the Long-Duration Anesthetic Butamben

Departments of Pathology, Anatomy, and Cell Biology (D.L.B.W., M.E.O.) and Biochemistry and Molecular Pharmacology (C.L.B.), Jefferson Medical College, Philadelphia, PA; and Department of Physiology, Leiden University Medical Center, Leiden, The Netherlands (D.L.B.W., D.L.Y.)

n-Butyl-p-aminobenzoate (BAB; butamben) is a long-duration anesthetic used for the treatment of chronic pain. Epidural administration of BAB is thought to reduce the electrical excitability of dorsal root nociceptor fibers by inhibiting voltage-gated ion channels. To further investigate this mechanism, we examined the effects of BAB on the potassium currents of acutely dissociated neurons from the rat dorsal root ganglion (DRG). These neurons express a rapidly inactivating A-type K⁺ current (I_A) that is resistant to tetraethylammonium (20 mM) but inhibited by 4-aminopyridine (5 mM). At low concentrations, BAB (1 µM) selectively inhibited the I_A component of DRG K⁺ current. The voltage dependence of activation and inactivation, kinetics of recovery from inactivation, and the pharmacology of the DRG I_A were similar to those of the Kv4 family of K⁺ channels. Reverse transcription-polymerase chain reaction was used to establish that the messages encoding for all three of the mammalian Kv4 channel subunits (Kv4.1–Kv4.3) were present in the rat DRG. BAB produced a high-affinity, partial inhibition of heterologously expressed Kv4.2 channels (K_D = 59 nM) but did not alter the kinetics or voltage sensitivity of gating. Substituting polar threonines for conserved hydrophobic residues of the S6 segment weakened BAB binding but did not alter the voltage-dependent gating of the Kv4.2 channel. At physiological pH, BAB is uncharged, suggesting that hydrophobic interactions may contribute to drug binding. The data support a mechanism in which BAB binds near the narrow cytoplasmic entrance of Kv4 channels and inhibits current by a pore blocking mechanism.

Address correspondence to: Dr. Michael E. O'Leary, Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College, 1020 Locust St., JAH 266, Philadelphia, PA 19107. E-mail: michael.oleary{at}jefferson.edu

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