Desensitization of the inhibition of the M-current in sympathetic neurons: effects of ATP analogs, polyanions, and multiple agonist applications.

Desensitization occurs when the response to a neurotransmitter receptor agonist wanes in the continued presence of agonist. In amphibian sympathetic neurons, both muscarinic and peptidergic receptor agonists inhibit a K+ current, the M-current (IM), and this inhibition desensitizes. We have studied the desensitization to substance P (SP) by whole-cell recordings from dissociated sympathetic neurons from bullfrogs. When ATP in the recording pipette was replaced with AMP-PNP, SP still inhibited IM, but no desensitization was observed, indicating that ATP hydrolysis is required for desensitization. Desensitization inhibitors of beta-adrenergic receptors did not block desensitization to SP. When a low dose of muscarine sufficient to inhibit IM, but not to elicit desensitization, was applied simultaneously with a desensitizing dose of SP, IM remained depressed and did not desensitize. Thus, there may be separate systems controlling desensitization for different agonists, or the enzyme(s) involved is "compartmentalized."