The membrane properties of isolated frog parathyroid cells were studied using perforated and conventional whole-cell patch-clamp techniques. Frog parathyroid cells displayed transient inward currents in response to depolarizing pulses from a holding potential of -84 mV. We analyzed the biophysical properties of the inward currents. The inward currents disappeared by the replacement of external Na+ with NMDG+ and were reversibly inhibited by 3 micromol l-1 TTX, indicating that the currents occur through the TTX-sensitive voltage-gated Na+ channels. Current density elicited by a voltage step from -84 mV to -24 mV was -80 pA pF-1 in perforated mode and -55 pA pF-1 in conventional mode. Current density was decreased to -12 pA pF-1 by internal GTPgammaS (0.5 mmol l-1), but not affected by internal GDPbetaS (1 mmol l-1). The voltage of half-maximum (V1/2) activation was -46 mV in both perforated and conventional modes. V1/2 of inactivation was -80 mV in perforated mode and -86 mV in conventional mode. Internal GTPgammaS (0.5 mmol l-1) shifted the V1/2 for activation to -36 mV and for inactivation to -98 mV. A putative endocannabinoid, 2-arachidonoylglycerol ether (2-AG ether, 50 micromol l-1) and a cannabinomimetic aminoalkylindole, WIN 55,212-2 (10 micromol l-1) also greatly reduced the Na+ current and shifted the V1/2 for activation and inactivation. The results suggest that the Na+ currents in frog parathyroid cells can be modulated by cannabinoids via a G protein-dependent mechanism.