Pharmacological inhibition of the M-current (original) (raw)

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 (_I_M), without appreciable effect on the delayed rectifier, Ca2+-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 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 _I_M. The intracellular transduction mechanism for _I_M inhibition is unknown.

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Selected References

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