K+ Channel Modulation in Rodent Neurohypophysial Nerve Terminals by Sigma Receptors and Not by Dopamine Receptors

1. Sigma receptors bind a diverse group of chemically unrelated ligands, including pentazocine, apomorphine (a dopamine receptor agonist) and haloperidol (a dopamine receptor antagonist). Although sigma binding sites are widely distributed, their physiological roles are poorly understood. Here, the whole-terminal patch-clamp technique was used to demonstrate that sigma receptors modulate K+ channels in rodent neurohypophysis. 2. Previous work suggested that dopamine type 4 (D4) receptors modulate neurohypophysial K+ current, so this study initially tested the role of dopamine receptors. Experiments using transgenic mice lacking D2, D3 or D4 receptors indicated that the reduction of K+ current by PPHT and U101958 (ligands thought to be selective for dopamine receptors) is not mediated by dopamine receptors. The sensitivity of the response to U101958 (a drug that binds to D4 receptors) was the same in both wild-type and D4 receptor-deficient mice. 3. Experiments with other ligands revealed a pharmacological signature inconsistent with any known dopamine receptor. Furthermore, dopamine itself (at 100 microM) had no effect. Thus, despite the activity of a number of putative dopamine receptor ligands, dopamine receptors play no role in the modulation of neurohypophysial K+ channels. 4. Because of the negative results regarding dopamine receptors, and because some of the dopamine receptors ligands used here are known to bind also to sigma receptors, experiments were conducted to test for the involvement of sigma receptors. In rat neurohypophysis the sigma receptor ligands SKF10047, pentazocine, and ditolylguanidine all reversibly inhibited K+ current in a concentration-dependent fashion, as did haloperidol and apomorphine (ligands that bind to both dopamine and sigma receptors). The activity of these and other ligands tested here matches the reported binding specificity for sigma receptors. 5. Fifteen candidate endogenous sigma receptor ligands, including biogenic amines (e.g dopamine and serotonin), steroids (e.g. progesterone), and peptides (e.g. neuropeptide Y), were screened for activity at the sigma receptor. All were without effect. 6. Haloperidol reduced K+ current proportionally at all voltages without shifting the voltage dependence of activation and inactivation. Sigma receptor ligands inhibited current through two distinct K+ channels, the A-channel and the Ca2+-dependent K+ channel. In rat, all drugs reduced current through both channels proportionally, suggesting that both channels are modulated by a single population of sigma receptors. In contrast, mouse peptidergic nerve terminals either have two receptors which are sensitive to these drugs, or a single receptor that is differentially coupled to ion channel function. 7. The inhibition of voltage-activated K+ current by sigma receptors would be expected to enhance the secretion of oxytocin and vasopressin from the neurohypophysis.