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, in cluding pentazocine, apomorphine (a dopamine receptor agonist) and haloperi dol (a dopamine receptor antagonist). Although sigma binding sites are wide ly distributed, their physiological roles are poorly understood. Here, the whole-terminal patch-clamp technique was used to demonstrate that sigma rec eptors modulate K+ channels in rodent neurohypophysis. 2. Previous work suggested that dopamine type 4 (D-4) receptors modulate ne urohypophysial K+ current, so this study initially tested the role of dopam ine receptors. Experiments using transgenic mice lacking D-2, D-3 or D-4 re ceptors indicated that the reduction of K+ current by PPHT and U101958 (lig ands thought to be selective for dopamine receptors) is not mediated by dop amine receptors. The sensitivity of the response to U101958 (a drug that bi nds to D-4 receptors) was the same in both wild-type and D-4 receptor-defic ient mice. 3. Experiments with other ligands revealed a pharmacological signature inco nsistent with any known dopamine receptor. Furthermore, dopamine itself (at 100 mu M) had no effect. Thus, despite the activity of a number of putativ e dopamine receptor ligands, dopamine receptors play no role in the modulat ion of neurohypophysial K+ channels. 4. Because of the negative results regarding dopamine receptors, and becaus e some of the dopamine receptors ligands used here are known to bind also t o sigma receptors, experiments were conducted to test for the involvement o f sigma receptors. In rat neurohypophysis the sigma receptor ligands SKF100 47, pentazocine, and ditolylguanidine all reversibly inhibited K+ current i n a concentration-dependent fashion, as did haloperidol and apomorphine (li gands that bind to both dopamine and sigma receptors). The activity of thes e and other ligands tested here matches the reported binding specificity fo r sigma receptors. 5. Fifteen candidate endogenous sigma receptor ligands, including biogenic amines (e.g. dopamine and serotonin), steroids (e.g. progesterone), and pep tides (e.g. neuropeptide Y), were screened for activity at the sigma recept or. All were without effect. 6. Haloperidol reduced K+ current proportionally at all voltages without sh ifting the voltage dependence of activation and inactivation. Sigma recepto r ligands inhibited current through two distinct K+ channels, the A-channel and the Ca2+-dependent K+ channel. In rat, all drugs reduced current throu gh both channels proportionally, suggesting that both channels are modulate d by a single population of sigma receptors. In contrast, mouse peptidergic nerve terminals either have two receptors which are sensitive to these dru gs, or a single receptor that is differentially coupled to ion channel func tion. 7. The inhibition of voltage-activated K+ current by sigma receptors mould be expected to enhance the secretion of oxytocin and vasopressin from the n eurohypophysis.