Sigma ligands stimulate the electrical activity of frog pituitary melanotrope cells through a G-protein-dependent inhibition of potassium conductances.

We have investigated the effects of sigma ligands [1,3-di(2-tolyl)guanidine (DTG) and (+)-pentazocine] on the electrical activity of cultured frog pituitary melanotrope cells by using the patch-clamp technique. DTG and (+)-pentazocine (10 microM each) induced a reversible depolarization associated with an increase in membrane resistance and action potential firing. In voltage-clamp experiments, DTG and (+)-pentazocine elicited inward currents whose intensity augmented with membrane depolarization. The currents vanished or reversed between -90 and -100 mV, at values close to the K+ equilibrium potential (E(K)+ = -102 mV). DTG (2-500 microM) and (+)-pentazocine (0.2-200 microM) reduced the outward delayed rectifier K+ current [IK (V)] in a dose-dependent manner with EC50 of 64 and 37 microM, respectively. In contrast, naloxone (50 microM) and pirenzepine (10 microM) did not affect the sigma ligand-induced inhibition of IK (V). Addition of guanosine-5'-O-(3-thiophosphate) in the pipette solution irreversibly sustained the DTG-induced current whereas guanosine-5'-O-(2-thiodiphosphate) virtually suppressed the response. Cholera toxin-pretreatment (1 microgram/ml; 18 hr) abolished the inward current and the inhibition of IK (V) induced by sigma ligands. In contrast, pretreatment with pertussis toxin (1 microgram/ml; 18 hr) had no effect. Taken together, these data indicate that DTG and (+)-pentazocine activate the electrical activity of cultured frog melanotrope cells by reducing both a tonic K+ current and a voltage-dependent [IK (V)] K+ conductance through the activation of a cholera toxin-sensitive G-protein.