Muscarinic modulation of calcium currents was studied in acutely isolated striatal neurons from the adult rat using the whole-cell configuration of the patch-clamp technique. Muscarinic agonists reduced calcium currents through two distinct signaling pathways. One pathway depended upon PTX-sensitive G-proteins and targeted N- and P-type currents. The other pathway depended upon PTX-insensitive G-proteins and was rendered inactive by high intracellular concentrations of BAPTA and targeted L-type currents. The modulation of N- and P-type currents was relieved by strong depolarizing prepulses, whereas the modulation of L-type currents was not. These findings support the proposition that parallel signaling pathways exist between muscarinic receptors and calcium channels.