Sigma receptor
The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP,SA 4503, ditolylguanidine, dimethyltryptamine, and siramesine.
Classification
σ–receptors were once thought to be a type of opioid receptor, because the d- stereoisomers of the benzomorphan class of opioid drugs reduced coughing, as do some other opioid derivatives such as dextromethorphan. However, such drugs had no clinically relevant affinities for μ (Mu), κ (kappa), or δ (Delta) receptors.
However, pharmacological testing indicated that the σ-receptors were activated by drugs completely unrelated to the opioids, and their function was unrelated to the function of the opioid receptors. For example, phencyclidine (PCP), and the antipsychotic haloperidol may interact with σ-receptors. Neither phencyclidine nor haloperidol have any appreciable chemical similarity to the opioids.
When the σ1 receptor was isolated and cloned, it was found to have no structural similarity to the opioid receptors. At this point, they were designated as a separate class of receptors.
Sigma-2 receptor
The sigma-2 receptor (σ2R) is a sigma receptor subtype which has been found highly expressed in malignant cancer cells, and is currently under investigation for its potential diagnostic and therapeutic uses. Originally, it was thought that the sigma receptors were a type of opiate receptor, due to its ability to bind ligands such as benzomorphans and PCP. Difficulties were found in distinguishing between the sigma-2 receptor and the NMDA receptors, though it is now known they have different distributions throughout the brain. The sigma-2 receptor in particular is more densely located in parts of the brain that are responsible for motor function and emotional response. It has been found to play a role in both hormone signaling and calcium signaling, in neuronal signaling, in cell proliferation and death, and in binding of antipsychotics. The position of the sigma-2 receptor has not yet been located on the human chromosome.
Classification
The sigma-2 receptor is a cytochrome related protein located in the lipid raft that is most commonly associated with P450 proteins, and is coupled with the PGRMC1 complex, EGFR, mTOR, caspases, and various ion channels. It was previously thought to be the same as the NMDA receptor, is non-opioid, does not translocate, and unlike the sigma-1 receptor, has not been cloned. The sigma-2 receptor is found in several areas of the brain, including high densities in the cerebellum, motor cortex, and substantia nigra, though it shows no homology with other proteins present in brain tissue. It is also highly expressed in the lungs, liver, and kidneys.
Sigma-1 receptor
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. In humans, the σ1 receptor is encoded by the SIGMAR1 gene.
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. It has been implicated in myriad phenomena, including cardiovascular function, schizophrenia, clinical depression, the effects of cocaine abuse, and cancer. Much is known about the binding affinity of hundreds of synthetic compounds to the σ1 receptor.
An endogenous ligand for the σ1 receptor has yet to be conclusively identified, but tryptaminergic trace amines, as well as neuroactive steroids such as dehydroepiandrosterone (DHEA) and pregnenolone all activate the receptor.
Characteristics
The σ1 receptor is defined by its unique pharmacological profile. In 1976 Martin reported that the effects of N-allylnormetazocine (SKF-10,047) could not be due to activity at the μ and κ receptors (named from the first letter of their selective ligands morphine and ketazocine, respectively) and a new type of opioid receptor was proposed; σ (from the first letter of SKF-10,047). However, ligands acting at this new “opioid” receptor were not blocked by the classical opioid antagonists naloxone and naltrexone. Consequently, the opioid classification was eventually dropped and the receptor was later termed the σ1 receptor. It was found to have affinity for the (+)-stereoisomers of several benzomorphans (e.g., (+)-pentazocine and (+)-cyclazocine), various structurally and pharmacologically distinct psychoactive chemicals such as haloperidol and cocaine, and neuroactive steroids like progesterone.
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