The sigma agonist 1,3-di-o-tolyl-guanidine directly blocks SK channels in dopaminergic neurons and in cell lines

作者：Lamy Cedric; Scuvee Moreau Jacqueline; Dilly Sebastien; Liegeois Jean Francois; Seutin Vincent^*

来源：European Journal of Pharmacology, 2010, 641(1): 23-28.

DOI：10.1016/j.ejphar.2010.05.008

• SK channel
• Sigma receptor
• DIG
• Dopaminergic neuron

Small conductance Ca(2+)-activated K(+) (SK) channels are widely expressed in the brain and underlie medium-duration afterhyperpolarizations (mAHPs) in many types of neurons. It was recently reported that the activation of sigma-1 (sigma(1)) receptors inhibits SK currents in rat hippocampus. Because many interactions between a receptors and brain dopaminergic systems have been reported, we set out to examine putative effects of a receptor ligands on the SK mediated rnAHP in midbrain dopaminergic neurons. We found that 1,3-di-o-tolyl-guanidine (DIG) inhibited the mAHP in a concentration-dependent manner (similar to 60% inhibition at 100 mu M), while other a receptor agonists (carbetapentane, (+)-SKF10047 and PRE-084) had little effect. Moreover, the effect of DTG was not affected by high concentrations of the sigma(1) receptor antagonist BD 1047. A role for sigma(2) receptors could also be excluded by the lack of effect of the sigma(2) receptor ligand 5-bromo-tetrahydroisoquinolinylbenzamide. These results argue against a coupling of a receptors to SK channels in dopaminergic neurons. We next hypothesized that DTG could directly block the channel. This hypothesis was tested in HEK-293 cells which were transiently transfected with rSK2 or hSK3 subunits. DIG inhibited the current flowing through both subtypes with mean IC(50)s similar to 200 mu M. This action was also unaffected by BD 1047. Other a receptor ligands had little or no effect. We conclude that DIG directly blocks SK channels. This pharmacological action may be important to consider in future experimental settings.

• 出版日期2010-9-1