J Physiol 332: 223-262

PMC: PMC1197396

Pharmacological inhibition of the M-current

Abstract

2. Muscarine (1-10 μM), D-ala^{LHRH (1-5 μM), UTP (50-100 μM) and Ba}^{(1-4 mM) selectively depressed the M-current (}I_M), without appreciable effect on the delayed rectifier, Ca^{-activated or transient outward currents (}I_K, I_C or I_A).

3. I_M-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 I_M. The kinetics and voltage sensitivity of residual I_M 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 I_M. 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. I_M was not modified by removing extracellular Ca^{, adding a selective Ca}^{-channel blocker (Cd}^{), adding 1 mM-dibutyryl cyclic AMP or 8′Br cyclic GMP, or by intracellular ionophoresis of Ca}^{, 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 I_M. The intracellular transduction mechanism for I_M inhibition is unknown.

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Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston, TX 77550, U.S.A.

^{Present address: Department of Neurobiology and Behaviour, State University of New York at Stony Brook. Long Island NY 11794 U.S.A.}

^{Present address: Department of Pharmacology, School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX U.K.}

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-ala^{LHRH (1-5 μM), UTP (50-100 μM) and Ba}^{(1-4 mM) selectively depressed the M-current (}I_M), without appreciable effect on the delayed rectifier, Ca^{-activated or transient outward currents (}I_K, I_C or I_A).3. I_M-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 I_M. The kinetics and voltage sensitivity of residual I_M 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 I_M. 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. I_M was not modified by removing extracellular Ca^{, adding a selective Ca}^{-channel blocker (Cd}^{), adding 1 mM-dibutyryl cyclic AMP or 8′Br cyclic GMP, or by intracellular ionophoresis of Ca}^{, 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 I_M. The intracellular transduction mechanism for I_M inhibition is unknown.