Evidence for Inhibitory Perturbations on the Amplitude, Gating, and Hysteresis of A-Type Potassium Current, Produced by Lacosamide, a Functionalized Amino Acid with Anticonvulsant Properties.

Lacosamide (Vimpat ® , LCS) is widely known as a functionalized amino acid with promising anti-convulsant properties; however, adverse events during its use have gradually appeared. Despite its inhibitory effect on voltage-gated Na + current ( I Na ), the modifications on varying types of ionic currents caused by this drug remain largely unexplored. In pituitary tumor (GH 3 ) cells, we found that the presence of LCS concentration-dependently decreased the amplitude of A-type K + current ( I K(A) ) elicited in response to membrane depolarization. The I K(A) amplitude in these cells was sensitive to attenuation by the application of 4-aminopyridine, 4-aminopyridine-3-methanol, or capsaicin but not by that of tetraethylammonium chloride. The effective IC 50 value required for its reduction in peak or sustained I K(A) was calculated to be 102 or 42 µM, respectively, while the value of the dissociation constant ( K D ) estimated from the slow component in I K(A) inactivation at varying LCS concentrations was 52 µM. By use of two-step voltage protocol, the presence of this drug resulted in a rightward shift in the steady-state inactivation curve of I K(A) as well as in a slowing in the recovery time course of the current block; however, no change in the gating charge of the inactivation curve was detected in its presence. Moreover, the LCS addition led to an attenuation in the degree of voltage-dependent hysteresis for I K(A) elicitation by long-duration triangular ramp voltage commands. Likewise, the I K(A) identified in mouse mHippoE-14 neurons was also sensitive to block by LCS, coincident with an elevation in the current inactivation rate. Collectively, apart from its canonical action on I Na inhibition, LCS was effective at altering the amplitude, gating, and hysteresis of I K(A) in excitable cells. The modulatory actions on I K(A) , caused by LCS, could interfere with the functional activities of electrically excitable cells (e.g., pituitary tumor cells or hippocampal neurons).