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Inhibition of the ATP‐sensitive potassium channel in the guinea pig substantia nigra by BMS 181100 is not mediated by a sigma‐binding site
Author(s) -
O'Callaghan J. F. X.,
Greenfield S. A.
Publication year - 1995
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.490420110
Subject(s) - substantia nigra , chemistry , pars compacta , biophysics , apamin , diazoxide , membrane potential , agonist , stereochemistry , potassium channel , biochemistry , receptor , endocrinology , dopamine , biology , dopaminergic , insulin
Quantitative autoradiography of brain tissue has revealed a high density of binding sites for the K‐ATP channel antagonists, the sulphonylureas, and for σ‐ligands in the substantia nigra (SN). In view of the high density of the two binding sites in the SN the possibility has been investigated that the K‐ATP channel and the σ‐binding site are functionally linked. The K‐ATP channel‐mediated membrane hyperpolarisation and decrease in input resistance produced by hypoxia and by the metabolic inhibitor, cyanide, in rostral substantia nigra pars compacta neurons are antagonised by the σ‐ligand BMS 181100. In addition, BMS 181100 antagonises activation of the K‐ATP channel by diazoxide; cromakalim is found to be without effect in these neurons. Antagonism of the cyanide‐induced hyperpolarisation is dose dependent and is observed at concentrations of the drug which have no observable effect on the resting membrane properties of the neurons. By contrast, the nonselective sigma ligands 1,3‐di‐O‐tolylguanidine (10 μM) and ( +)‐3‐(3‐hydroxyphenyl)‐N‐(1 ‐propyl)piperidine (100 μM), and the selective σl‐ligand (+)‐pentazocine 5‐10 μM) have no effect on the cyanide‐induced hyperpolarisation. 5‐HT (50‐100 μM) and the selective 5‐HT1A receptor agonist 8‐OH‐DPAT (50 μM) also fail to antagonise the cyanideinduced hyperpolarisation. The antagonism of the cyanide‐induced hyperpolarisation by BMS 181100 persists in the presence of tetrodotoxin (1 μM) and in the presence of high concentrations of (+)‐3‐(3‐hydroxyphenyl)‐N‐(1‐propyl)piperidine, but not under conditions of reduced calcium (0.1‐0.2 mM) and raised magnesium (6 mM) concentrations, which block synaptic transmission. It is concluded that in substantia nigra phasic neurons the σ‐binding site does not regulate activation of the ATP‐sensitive channel. However, BMS 181100 antagonises K‐ATP channel activation in these neurons independently of σ‐binding sites and 5‐HT receptors. This action of BMS 181100 is TTX insensitive and Ca 2+ dependent. © 1995 Wiley‐Liss, Inc.