Dynamic Interaction between Sigma-1 Receptor and Kv1.2 Shapes Neuronal and Behavioral Responses to Cocaine

Abstract

Summary The sigma-1 receptor (Sig-1R), an endoplasmic reticulum (ER) chaperone protein, is an inter-organelle signaling modulator that potentially plays a role in drug-seeking behaviors. However, the brain site of action and underlying cellular mechanisms remain unidentified. We found that cocaine exposure triggers a Sig-1R-dependent upregulation of D-type K+ current in the nucleus accumbens (NAc) that results in neuronal hypoactivity, and thereby enhances behavioral cocaine response. Combining ex vivo and in vitro studies, we demonstrated that this neuroadaptation is caused by a persistent protein-protein association between Sig-1Rs and Kv1.2 channels, a phenomenon that is associated to a redistribution of both proteins from intracellular compartments to the plasma membrane. In conclusion, the dynamic Sig-1R - Kv1.2 complex represents a novel mechanism that shapes neuronal and behavioral response to cocaine. Functional consequences of Sig-1R binding to K+ channels may have implications for other chronic diseases where maladaptive intrinsic plasticity and Sig-1Rs are engaged.

SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness

“…hERG recruitment following cell contact with ECM requires the presence of Sig1R that behaves as a chaperone driving hERG to the plasma membrane. In agreement with this hypothesis, we and others have shown that Sig1R directly binds with hERG and other ion channels, promoting their activity and their membrane expression (15,19,25). In the context of ECM stimulation, hERG current was increased without modifying channel maturation ratio (Supplementary Fig.…”

“…21,22). Therefore, Sig1R has been associated to many pathophysiologic contexts, including stroke, neurodegenerative diseases, pain, or cocaine addiction (15). Interestingly, Sig1R is overexpressed in cancer cell lines (23), and we have shown that it functions as a chaperone enhancing maturation and membrane expression of hERG by a direct physical interaction (24,25).…”

“…Our interest focused on the sigma 1 receptor (Sig1R), a 25-kDa chaperone protein mainly expressed in the brain and residing at the endoplasmic reticulum (ER)-mitochondria interface (mitochondria ER-associated membrane, MAM; refs. [13][14][15][16]. Sig1R functionally interacts with ion channels from various families, including voltage-dependent channels (17)(18)(19), volume-regulated chloride channels, acid-sensing ion channels (20), and Nmethyl-D-aspartic acid receptor (NMDA; refs.…”

Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope

“…The Sig-1R can translocate from the MAM to plasma membrane of the cell to regulate ion channels and receptors on the plasma membrane (8,(11)(12)(13)(14). Cocaine is a Sig-1R agonist (3) that causes the dissociation of Sig-1R from its cognate binding partner BiP (3,8), and consequently the translocation of Sig-1Rs to the plasma membrane, where Sig-1Rs interact with voltage-gated potassium channel subfamily A member 2 (Kv1.2) to shape the neuronal and behavioral responses to cocaine (15).…”

Sigma-1 receptors modulate neonatal Nav1.5 ion channels in breast cancer cell lines

“…This hypothesis was further strengthened by a recent report showing that cocaine exposure induces a persistent protein-protein association between the sigma-1 receptor and K v 1.2 channel. This phenomenon was associated with a redistribution of both proteins from the intracellular compartments to the plasma membrane (Kourrich et al 2013).…”