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

Abstract

Most physiological effects of 1 receptor ligands are sensitive to pertussis toxin, suggesting a coupling with cell membrane-bound G proteins. However, the cloning of the 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 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 ␤ 1 and ␤ 2 isoforms and the phosphorylation of a protein of the same molecular weight as the cloned 1 receptor lead to a desensitization of the 1 motor response. Our results indicate that the intracellular 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.

Involvement of the Sigma1 Receptor in Cocaine-induced Conditioned Place Preference Possible Dependence on Dopamine Uptake Blockade

“…Considering the most recent hypotheses regarding its cellular function, the sigma 1 receptor plays a significant role in second messenger cascades, mechanisms involved in some effects of cocaine (Hayashi et al 2000;Morin-Surun et al 1999;Hyman 1996;Pierce et al 1998;Valjent et al 2000). Activation of the sigma 1 receptor results in its translocation from the endoplasmic reticulum membrane to the vicinity of the plasma membrane and the regulation of several components implicated in plasma membranebound signal transduction, including protein kinase C (Morin-Surun et al 1999). Such a mechanism as demonstrated in hypoglossal neurons in the brain stem may also occur in dopaminergic neurons and may explain the rapid effects of sigma 1 receptor agonists/antagonists.…”

“…The biological relevance of this receptor is supported by the correlation observed between functional and behavioral effects of selective drugs and affinities at the sigma 1 binding sites (for review, see Maurice et al 1999). The sigma 1 receptor mediates a potent modulation of several neurotransmitter systems by affecting intracellular second messengers systems, particularly Ca 2 ϩ mobilization (Morin-Surun et al 1999;Hayashi et al 2000). Once cocaine's relative potency to inhibit the binding of sigma 1 receptor radiotracers had been established, with a Ki about 1.7 M (Ritz and George 1993), the involvement of the sigma 1 receptor as a possible target of cocaine was suggested.…”

Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1-41 Against Amyloid β25–35-Induced Toxicity in Mice

“…Numerous s 1 protein activators including ( + )-SKF-10 047, ( + )-pentazocine, SA4503, or PRE-084 attenuated Ab 25-35 -induced learning impairments (Maurice et al, 1998;Meunier et al, 2006). Indeed, activation of the s 1 protein rapidly results in amplification of Ca 2 + mobilization from intracellular stores, facilitating Ca 2 + -dependent intracellular pathways and activation of intracellular kinases (Morin-Surun et al, 1999;Hayashi and Su, 2001;Dong et al, 2005). In turn, s 1 protein activators increase hippocampus glutamatergic transmission by facilitating glutamate release, activation of glutamate receptors and long-term potentiation (Monnet et al, 1992;Dong et al, 2005).…”

“…Upon ER Ca 2 + depletion or by ligand stimulation, the s 1 protein dissociates from GRP78/BiP, leading to a prolonged Ca 2 + signaling into mitochondria by IP 3 receptors (Hayashi and Su, 2007). Under intracellular Ca 2 + signaling disruption and subsequent ER stress, the s 1 protein translocates, to reach plasma membrane, recruiting Ca 2 + -dependent intracellular cascades (Morin-Surun et al, 1999). On the plasma membrane, it contributes to form or modify the composition of lipid-rich microdomains, socalled lipid rafts Su, 2001, 2003).…”

Sigma-1R Agonist Improves Motor Function and Motoneuron Survival in ALS Mice

“…This receptor has the ability to translocate from the endoplasmic reticulum to the plasma membrane and mitochondria-associated membranes [7,11,12]. In the nervous system, sigma-1R mediates regulation of several processes, such as neuritogenesis, K + channels, and N-methyl-D-aspartate (NMDA) receptors activity, Ca 2+ homeostasis, and microglial activity.…”