Common ionic mechanisms of excitation by substance P and other transmitters in guinea-pig submucosal neurones.

1. Intracellular recordings were made from submucosal neurones and single-electrode voltage-clamp methods were used to record membrane currents. The actions of substance P (SP), 5-hydroxytryptamine (5-HT), muscarine, vasoactive intestinal polypeptide (VIP), forskolin and nerve stimulation were studied. 2. Substance P, 5-HT (in the presence of 5-HT3 receptor antagonists), muscarine, VIP, forskolin and slow excitatory synaptic transmission all produced identical responses: an inward current associated with a membrane conductance decrease at the resting potential. The actions of any one occluded the actions of any other and all responses were pertussis-toxin insensitive. 3. These agonists produced a voltage-independent decrease in a 'leak' potassium conductance between -40 and -120 mV in 14% of neurones. 4. These agonists decreased a voltage-dependent, calcium-activated potassium conductance between -40 and -80 mV in all other (86%) neurones. The agonists still evoked an inward current without apparent conductance change at potentials between -90 and -130 mV. 5. In a low calcium solution containing cobalt or cadmium, the agonists produced an inward current associated with a conductance increase from -40 to -120 mV. Ion replacement studies indicated this current was due to an increase in a cation-selective (mainly sodium) conductance. 6. The agonists also reduced the inwardly rectifying potassium current that is activated by somatostatin and alpha 2-adrenoceptor agonists in these neurones. The agonists did not alter the inwardly rectifying potassium current that is present in these neurones in the absence of somatostatin or alpha 2-agonists. 7. Thus, SP, 5-HT, muscarine, VIP and the release of slow excitatory transmitters all appear to act through a common intracellular transduction pathway, an increase in adenylate cyclase. This results in an activation of a sodium-selective cation current and an inhibition of three distinct potassium conductances: the background potassium conductance, the calcium-activated potassium conductance and the inwardly rectifying potassium conductance activated by somatostatin and alpha 2-adrenoceptor agonists.