Arachidonic acid metabolites as mediators of somatostatin-induced increase of neuronal M-current

Abstract

THE M-current (I_M) is a time- and voltage-dependent K⁺ current that persists at slightly depolarized membrane potentials¹. I_M is reduced by muscarinic cholinergic agonists and certain peptides, and is thought to be responsible in part for the slow and late slow excitatory postsynaptic potentials in sympathetic neurons^1–3. Recently, we reported⁴ that I_M in hippocampal neurons was also augmented by somatostatin-14 and -28 suggesting that two different receptors reciprocally regulate one neuronal channel type (ref. 4; see also ref. 5). Muscarinic effects on I_M may be mediated by various components of the phosphatidylinositol phosphate pathway^6,7. We now report the involvement of a different second messenger pathway, that generated by phospholipase A₂^8–10, in the somatostatin-induced augmentation of I_M in hippocampal cells. This pathway generates arachidonic acid from which leukotrienes can be produced by lipoxygenases. We find that the I_M-augmenting effects of somatostatin are abolished by two substances that can inhibit phospholipase A₂¹¹, quinacrine and 4-bromophenacyl bromide, and that both arachidonic acid and leukotriene C₄ mimic the effects of somatostatin-14 on hippocampal pyramidal neurons in vitro. Arachidonic and somatostatin effects are blocked by a lipoxygenase inhibitor, implicating an arachidonic acid metabolite, perhaps a leukotriene, in the somatostatin effect.