Pharmacological inhibition of the M‐current

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Abstract
1. The effects of muscarinic agonists, luteinizing hormone‐releasing hormone (LHRH) analogues, uridine triphosphate (UTP) and divalent cations on K+‐currents in voltage‐clamped bullfrog sympathetic neurones have been studied. 2. Muscarine (1‐10 μM), D‐ala6 LHRH (1‐5 μM), UTP (50‐100 μM) and Ba2+ (1‐4 mM) selectively depressed the M‐current (IM), without appreciable effect on the delayed rectifier, Ca2+‐activated or transient outward currents (IK, IC or IA). 3. IM‐inhibition was characterized by: (a) elimination of slow current relaxations accompanying voltage jumps in the membrane potential range ‐30 to ‐60 mV; (b) reduced voltage‐dependent chord conductance over this range with no change in the voltage‐independent chord conductance at more negative membrane potentials; (c) suppression of outward rectification in the steady‐state current—voltage curve between ‐70 and ‐25 mV; and (d) development of an inward current which increased in amplitude between ‐70 and ‐20 mV in proportion to the decrease in steady‐state IM. The kinetics and voltage sensitivity of residual IM were unchanged. 4. The magnitude of the inward current produced by muscarine or LHRH could be accounted for quantitatively by the reduction in steady‐state IM. No increase in leak current could be detected in the range ‐60 to ‐30 mV. In two cells muscarine (10 μM) increased the leak current and conductance at ‐70 to ‐100 mV, but not at more depolarized levels. 5. IM was not modified by removing extracellular Ca2+, adding a selective Ca2+‐channel blocker (Cd2+), adding 1 mM‐dibutyryl cyclic AMP or 8′Br cyclic GMP, or by intracellular ionophoresis of Ca2+, 8′Br cyclic GMP, dibutyryl cyclic AMP, GTP‐γ‐S or S‐adenosylmethionine. 6. It is concluded that the principal effects of these agents in unclamped neurones — depolarization, increased input resistance, reduced outward rectification and increased excitability — are due entirely to a selective inhibition of IM. The intracellular transduction mechanism for IM inhibition is unknown.