Suppression of a nonselective cation conductance by substance P in cochlear outer hair cells

Substance P (SP) hyperpolarizes outer hair cells (OHCs) of guinea pig cochlea. The cellular mechanisms of the SP response were investigated with the whole cell patch-clamp technique. SP induced outward currents in a dose-dependent manner at a holding potential of -60 mV in a concentration range between 3 x 10(-6) and 10(-4) M. SP decreased slope conductance between -60 and +20 mV. Ion substitutions in the external medium revealed that SP suppresses nonselective cation conductance with high permeability for Ca2+. The relative ion permeability of the channel modulated by SP was as follows: Ca2+ > Li+ approximately Cs+ approximately Na+ > Tris+. The potency of the agonist action was as follows: SP >> neurokinin A > neurokinin B. Peptide antagonists induced currents similar to those of SP. CP-96345, a selective nonpeptide antagonist for the neurokinin type 1 receptor, did not inhibit the SP-induced current. Intracellular dialysis of guanosine 5'-O-(2-thiodiphosphate) and pertussis toxin (PTX) suggests that a PTX-insensitive G protein is involved in the SP response. Neither the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid nor staurosporine (10(-6) M) affects the SP response. Local application of SP by a puffer pipette indicates that the SP receptors are distributed along the side of the OHC. These results suggest the possibility that the action of SP on the OHCs may not be mediated by the tachykinin receptors but rather by a tachykinin receptor-independent pathway. It is proposed that SP suppresses the nonselective cation conductance in the lateral wall of OHCs via a PTX-insensitive G protein.