REGULATION OF THE RESPONSES TO GONADOTROPIN-RELEASING-HORMONE, MUSCARINE AND SUBSTANCE-P IN SYMPATHETIC NEURONS BY CHANGES IN CELLULAR-CONSTITUENTS AND INTRACELLULAR APPLICATION OF PEPTIDE-FRAGMENTS OF THE SUBSTANCE-P RECEPTOR

The effects of alterations of intracellular constituents on the action s of three agonists [gonadotropin-releasing hormone, muscarine and sub stance P (SP)] on the M-type potassium current in bullfrog sympathetic neurons were examined. Application of maximal concentrations of each agonist resulted in inhibition of M-current followed by desensitizatio n. Desensitization was greatest during SP application, less with gonad otropin-releasing hormone and least after muscarine. Recovery after ag onist washout was greatest for SP, less for muscarine and least for go nadotropin-releasing hormone. The effects of varying intrapipette pH, [ATP], Ca buffer and free Ca on inhibition by each of the agonists, de sensitization and recovery were tested. Comparison of the effects of d ifferent intracellular constituents showed that desensitization and re covery are distinct phenomena. Desensitization was greatest with 3 mM ATP in the pipette and was enhanced when pyruvate and glucose were add ed extracellularly. Two synthetic peptides, comprising amino acids 325 -360 and 361-375, respectively, of the carboxyl tail of the rat SP rec eptor inhibited desensitization to SP, but not to the other agonists. A third peptide homologous to residues 376-407 and a peptide from the extracellular portion of the receptor (residues 168-179) did not affec t desensitization. This suggests that the portion of the carboxyl tail of the SP receptor from amino acids 325-375 is involved in desensitiz ation.