Inhibitory effect of the selective serotonin reuptake inhibitor paroxetine on human Kv1.3 channels

Paroxetine is one of the most effective selective serotonin reuptake inhibitors used to treat depressive and panic disorders that reduce the viability of human T lymphocytes, in which Kv1.3 channels are highly expressed. We examined whether paroxetine could modulate human Kv1.3 channels acutely and directly with the aim of un-derstanding the biophysical effects and the underlying mechanisms of the drug. Kv1.3 channel proteins were expressed in Xenopus oocytes. Paroxetine rapidly inhibited the steady-state current and peak current of these channels within 6 min in a concentration-dependent manner; IC(50)s were 26.3 mu M and 53.9 mu M, respectively, and these effects were partially reversed by washout, which excluded the possibility of genomic regulation. At the same test voltage, paroxetine blockade of the steady-state currents was higher than that of the peak currents, and the inhibition of the steady-state current increased relative to the degree of depolarization. Paroxetine decreased the inactivation time constant in a concentration-dependent manner, but it did not affect the activation time constant, which resulted in the acceleration of intrinsic inactivation without changing ultrarapid activation. Blockade of Kv1.3 channels by paroxetine exhibited more rapid inhibition at higher activation frequencies showing the use-dependency of the blockade. Overall, these results show that paroxetine directly suppresses human Kv1.3 channels in an open state and accelerates the process of steady-state inactivation; thus, we have revealed a biophysical mechanism for possible acute immunosuppressive effects of paroxetine.