Journal of Neuroscience, Vol 14, 7053-7066, Copyright © 1994 by Society for Neuroscience
On the role of arachidonic acid in M-current modulation by muscarine in bullfrog sympathetic neurons
A Villarroel
Howard Hughes Medical Institute, Department of Neurobiology and Behavior, SUNY at Stony Brook 11794-5230.
The modulation by muscarine or LHRH of the potassium M-current (IM) in
whole-cell voltage-clamped bullfrog sympathetic neurons presents an initial
phase of current reduction, followed, after agonist removal, by a transient
enhancement or "overrecovery." Employing a fast solution exchange system,
an inhibitory process and an enhancing process were distinguished
kinetically. The extent of overrecovery increased with the extent of the
preceding inhibition. The rate and degree of inhibition increased with the
concentration of agonist. In contrast, the rate of recovery and the extent
of overrecovery were independent. The half-lives of the inhibitory and
enhancing processes were 21 and 53 sec, respectively. Several observations
suggest that arachidonic acid (AA) may be involved in overrecovery: (1) AA
enhanced IM in a dose- dependent and reversible manner, with an IC50 of 2.8
microM. (2) Muscarine inhibited the A-current (IA), a potassium current
that is blocked by AA. (3) Phospholipase A2 inhibitors (quinacrine and
bromophenacyl bromide) and a lipoxygenase inhibitor (nordihydroguaiaretic
acid) prevented overrecovery, without affecting the rate or extent of IM
inhibition significantly. However, kinetic analysis indicates that these
drugs were preventing overrecovery by prolonging the half-life of the
inhibitory process to > 80 sec (e.g., not necessarily by blocking the
enhancing pathway). In addition, the extent of IA inhibition was less than
expected if AA was mediating both IM enhancement and IA inhibition. The
observed relation between extent and rate of overrecovery, and the action
of arachidonic acid metabolism inhibitors can be accounted for by a model
proposing that the agonist alters the equilibrium between three pools of
M-channels.