SUBSTANCE-P SUPPRESSES GABA(A) RECEPTOR FUNCTION VIA PROTEIN-KINASE-CIN PRIMARY SENSORY NEURONS OF BULLFROGS

1. The effects of substance P (SP) and related tachykinins on the func tion of gamma-aminobutyric acid-A (GABA(A)) receptors were examined in acutely dissociated neurones of bullfrog dorsal root ganglia (DRG) by using whole-cell voltage-clamp techniques. 2. Application of SP (10 n M to 1 mu M) depressed inward currents produced by GABA(A) receptor ac tivation (I-GABA). Neurokinin A (NKA) and neurokinin B (NKB) also depr essed I-GABA; the rank order of agonist potency was SP>NKA>NKB. Spanti de ([D-Arg(1), D-Trp(7,9), Leu(11)]SP) and L-703,606, NK1 receptor ant agonists, blocked the SP-induced depression of I-GABA. 3. SP irreversi bly depressed I-GABA, when neurones were intracellularly dialysed with GTP gamma S. Intracellular application of GDP beta S prevented the SP -induced depression of I-GABA. Pertussis toxin (PTX) did not block the inhibitory effect of SP on I-GABA. 4. The depression of I-GABA produc ed by SP was inhibited by H-7 and PKC(19-36), protein kinase C(PKC) in hibitors, but not by H-9 and HA-1004, protein kinase A inhibitors. I-G ABA was suppressed by application of sn-1,2-dioctanoyl glycerol(DOG), a PKC activator. 5. It is concluded that activation of neurokinin-(1) (NK1) receptors downregulates the function of the GABA(A) receptor of primary sensory neurones through a PTX-insensitive G-protein. PKC may be involved in the transduction pathway of the tachykinin-induced inhi bition of the GABA(A) receptor.