Sigma-1 Receptor

Pathway Information

The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor [1]. In humans, the σ1 receptor is encoded by the SIGMAR1 gene [2][3].

σ1 receptor modulators (such as E1R) have been demonstrated to be procognitive and promising candidates for developing nootropic compounds.

The σ1 receptor is a transmembrane protein expressed in many different tissue types. It is particularly concentrated in certain regions of the central nervous system [4]. It has been implicated in several phenomena, including cardiovascular function, schizophrenia, clinical depression, the effects of cocaine abuse, bipolar disorder, and cancer [5][6]. Much is known about the binding affinity of hundreds of synthetic compounds to the σ1 receptor.

PAM (like E1R) or agonists like DMT, memantine, opipramol, fluoxetine, allopregnanolone, fluvoxamine, PRE084, DXM (neurotoxic and is an SRI), 3-MeO-PCP, cariprazine, donepezil (60% occupancy at 5 mg) and SJW are the most effective ligands for this receptor. Both PAMs and agonists potentiate dopaminergic transmission (which can be synergistic with stimulants). σ1 receptors modulate dopamine, μ-opioid, κ-opioid, NMDA and LTP transmission. Fluvoxamine and opipramol are the most potent σ1 agonists available. σ1 activation also improves plasticity by potentiating NMDA and Ca2+ transmission.