Intracellular σ(1) receptor modulates phospholipase C and protein kinase C activities in the brainstem

Most physiological effects of σ(1) receptor ligands are sensitive to pertussis toxin, suggesting a coupling with cell membrane-bound G proteins. However, the cloning of the σ(1) receptor has allowed the identification of an intracellular protein anchored on the endoplasmic reticulum. Here, we show, using the isolated adult guinea pig brainstem preparation, that activation of the σ(1) receptor results in its translocation from the cytosol to the vicinity of the cell membrane and induces a robust and rapid decrease in hypoglossal activity, which is mediated by phospholipase C. The subsequent activation of protein kinase C β(1) and β(2) isoforms and the phosphorylation of a protein of the same molecular weight as the cloned σ(1) receptor lead to a desensitization of the σ(1) motor response. Our results indicate that the intracellular σ(1) receptor regulates several components implicated in plasma membrane-bound signal transduction. This might be an example of a mechanism by which an intracellular receptor modulates metabotropic responses.