Sigma receptors modulate nicotinic receptor function in adrenal chromaffin cells

Area of Science:

• Neuroscience
• Pharmacology
• Cell Biology

Background:

• The physiological roles and mechanisms of sigma (sigma) receptors remain largely unknown.
• Understanding sigma receptor ligand interactions is crucial for pharmacology.

Purpose of the Study:

• To investigate the cellular mechanism of sigma receptor ligands.
• To explore the interaction between sigma receptors and nicotinic acetylcholine receptors in catecholamine release.

Main Methods:

• Noncompetitive inhibition assays of nicotine-stimulated catecholamine release from bovine adrenal chromaffin cells.
• Radioligand binding assays using selective sigma 1 receptor ligands.
• Measurement of intracellular calcium ([Ca2+]i) in response to nicotine and sigma ligands.
• Analysis of radioligand ([3H](+)pentazocine) association kinetics with adrenal medullary homogenates.

Main Results:

• Sigma receptor ligands noncompetitively inhibited nicotine-stimulated catecholamine release in a concentration-dependent manner.
• Ligand potency for inhibiting catecholamine release correlated with sigma 1 receptor binding affinity.
• Sigma ligands inhibited nicotine-induced increases in intracellular calcium.
• Nicotine accelerated the association of a sigma 1 selective radioligand to adrenal medullary homogenates, suggesting allosteric modulation.

Conclusions:

• Sigma 1 receptor selective ligands modulate the actions of nicotinic acetylcholine receptor agonists in bovine chromaffin cells.
• Sigma 1 receptors are closely associated with and allosterically modulated by nicotinic acetylcholine receptors.
• This interaction provides a cellular mechanism for the pharmacological effects of sigma receptor ligands.