Allosteric Modulation of Opioid G-Protein Coupled Receptors by Sigma Receptors.

Since their proposal in 1976, the concept of sigma receptors has been continually evolving. Initially thought to be a member of the opioid receptor family, molecular studies have now identified its genes and established its structure crystallographically. Much effort has now revealed its importance as a chaperone in the endoplasmic reticulum, but its functions extend beyond this. Sigma receptors have been associated with a host of signaling systems. Evidence over the past 20 years has established the modulatory effects of sigma ligands on opioid systems. Despite their inability to bind directly to opioid receptors, sigma ligands can modulate opioid analgesia in vivo and signal transduction mechanisms in vitro. Furthermore, sigma receptors can physically associate with GPCRs. Together, these findings show that sigma ligands can function as allosteric modulators of GPCR function through their association with the sigma receptors, which are in direct physical association with opioid receptors, members of the G-protein coupled family of receptors.