Sigma-1 receptor
Encyclopedia
The sigma-1 receptor is a chaperone protein at the endoplasmatic reticulum (ER) that modulates calcium signaling
through the IP3 receptor. In humans, the sigma-1 receptor is encoded by the SIGMAR1 gene
.
The sigma-1 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 sigma-1 receptor.
An endogenous ligand
for the sigma-1 receptor has yet to be conclusively identified, but the trace amine
and hallucinogen dimethyltryptamine
(DMT), as well as neuroactive steroid
s such as dehydroepiandrosterone
(DHEA) and pregnenolone
, can all activate the receptor.
was proposed. However, ligands to this new “opioid” receptor could not be blocked by opioid antagonists naloxone
and naltrexone
. Consequently, the opioid classification was eventually dropped and the receptor was later termed the sigma-1 receptor. It was found to have affinity for a number of specific stereoisomers (e.g., (+)-pentazocine
and (+)-cyclazocine
), a diverse group of psychoactive chemicals such as haloperidol
and cocaine
, and neuroactive steroid
s like progesterone
.
contractility, and inhibition of voltage gated K+ channels
. The reasons for these effects are not well understood, even though sigma-1 receptors have been linked circumstantially to a wide variety of signal transduction pathways. Links between sigma-1 receptors and G-proteins have been suggested such as sigma-1 receptor antagonists showing GTP-sensitive high affinity binding , there is also, however, some evidence against a G-protein coupled hypothesis. The sigma-1 receptor has been shown to appear in a complex with voltage gated K+ channels (Kv1.4 and Kv1.5), leading to the idea that sigma-1 receptors are auxiliary subunits. Sigma-1 receptors apparently co-localize with IP3
receptors on the endoplasmic reticulum
. Also, sigma-1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes. The wide scope and effect of ligand binding on sigma-1 receptors has led some to believe that sigma-1 receptors are intracellular signal transduction amplifiers.
were created in 2009 to study the effects of endogenous DMT. Strangely, the mice demonstrated no overt phenotype. As expected, however, they did lack locomotor response to the sigma ligand (+)-SKF-10,047 and displayed reduced response to formalin induced pain. Speculation has focused on the ability of other receptors in the sigma family (e.g., sigma-2, with similar binding properties) to compensate for the lack of sigma-1 receptor.
Agents exist that have high σ1 affinity but either lack subtype selectivity or have high affinity at other binding sites, thus being more or less dirty
/multifunctional, like haloperidol
. Furthermore, there is a wide range of agents with an at least moderate σ1 involvement in their binding profile.
Calcium signaling
Calcium is a common signaling mechanism, as once it enters the cytoplasm it exerts allosteric regulatory effects on many enzymes and proteins...
through the IP3 receptor. In humans, the sigma-1 receptor is encoded by the SIGMAR1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
The sigma-1 receptor is a transmembrane protein
Transmembrane protein
A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
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
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, clinical depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, the effects of cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
abuse, and cancer. Much is known about the binding affinity of hundreds of synthetic compounds to the sigma-1 receptor.
An endogenous ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
for the sigma-1 receptor has yet to be conclusively identified, but the trace amine
Trace amine
Trace amines are endogenous compounds structurally related to classical biogenic amines, such as catecholamines, serotonin and histamine. Trace amines include p-tyramine, β-phenylethylamine, tryptamine, octopamine, and 3-iodothyronamine, and are found in the nervous systems of animals from insects...
and hallucinogen dimethyltryptamine
Dimethyltryptamine
N,N-Dimethyltryptamine is a naturally occurring psychedelic compound of the tryptamine family. DMT is found in several plants, and also in trace amounts in humans and other mammals, where it is originally derived from the essential amino acid tryptophan, and ultimately produced by the enzyme INMT...
(DMT), as well as neuroactive steroid
Neuroactive steroid
Neuroactive steroids rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels. In addition, these steroids may also exert effects on gene expression via intracellular steroid hormone receptors...
s such as dehydroepiandrosterone
Dehydroepiandrosterone
5-Dehydroepiandrosterone is a 19-carbon endogenous steroid hormone. It is the major secretory steroidal product of the adrenal glands and is also produced by the gonads and the brain. DHEA is the most abundant circulating steroid in humans....
(DHEA) and pregnenolone
Pregnenolone
Pregnenolone is a steroid hormone involved in the steroidogenesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. As such it is a prohormone. Pregnenolone sulfate is a GABAA antagonist and increases neurogenesis in the hippocampus.-Chemistry:Like other steroids,...
, can all activate the receptor.
Characteristics
The sigma-1 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 μ and κ receptors and a new type of opioid receptorOpioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...
was proposed. However, ligands to this new “opioid” receptor could not be blocked by opioid antagonists naloxone
Naloxone
Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...
and naltrexone
Naltrexone
Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia and Depade...
. Consequently, the opioid classification was eventually dropped and the receptor was later termed the sigma-1 receptor. It was found to have affinity for a number of specific stereoisomers (e.g., (+)-pentazocine
Pentazocine
Pentazocine is a synthetically prepared prototypical mixed agonist-antagonist narcotic drug of the benzomorphan class of opioids used to treat moderate to moderately severe pain...
and (+)-cyclazocine
Cyclazocine
Cyclazocine is a mixed opioid agonist/antagonist related to dezocine, pentazocine and phenazocine. This family of opioid drugs is called the benzomorphans or benzazocines.- Use :...
), a diverse group of psychoactive chemicals such as haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
and cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
, and neuroactive steroid
Neuroactive steroid
Neuroactive steroids rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels. In addition, these steroids may also exert effects on gene expression via intracellular steroid hormone receptors...
s like progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
.
Structure
The sigma-1 receptor is an integral membrane protein with 223 amino acids. Interestingly, it does not bear a resemblance to any other known mammalian protein. It does, however, share 30% identity and 66% homology with fungal sterol isomerase, while at the same time lacking sterol isomerase enzymatic activity. Hydropathy analysis of the sigma-1 receptor indicates three hydrophobic regions, with some evidence for two transmembrane segments. A crystal structure of the sigma-1 receptor is unavailable.Functions
A variety of specific physiological functions have been attributed to the sigma-1 receptor. Chief among these are modulation of Ca2+ release, modulation of cardiac myocyteMyocyte
A myocyte is the type of cell found in muscles. They arise from myoblasts.Each myocyte contains myofibrils, which are long, long chains of sarcomeres, the contractile units of the cell....
contractility, and inhibition of voltage gated K+ channels
Voltage-gated potassium channel
Voltage-gated potassium channels are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state....
. The reasons for these effects are not well understood, even though sigma-1 receptors have been linked circumstantially to a wide variety of signal transduction pathways. Links between sigma-1 receptors and G-proteins have been suggested such as sigma-1 receptor antagonists showing GTP-sensitive high affinity binding , there is also, however, some evidence against a G-protein coupled hypothesis. The sigma-1 receptor has been shown to appear in a complex with voltage gated K+ channels (Kv1.4 and Kv1.5), leading to the idea that sigma-1 receptors are auxiliary subunits. Sigma-1 receptors apparently co-localize with IP3
Inositol triphosphate
Inositol trisphosphate or inositol 1,4,5-trisphosphate , together with diacylglycerol , is a secondary messenger molecule used in signal transduction and lipid signaling in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell...
receptors on the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
. Also, sigma-1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes. The wide scope and effect of ligand binding on sigma-1 receptors has led some to believe that sigma-1 receptors are intracellular signal transduction amplifiers.
Knockout mice
Sigma-1 receptor knockout miceKnockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
were created in 2009 to study the effects of endogenous DMT. Strangely, the mice demonstrated no overt phenotype. As expected, however, they did lack locomotor response to the sigma ligand (+)-SKF-10,047 and displayed reduced response to formalin induced pain. Speculation has focused on the ability of other receptors in the sigma family (e.g., sigma-2, with similar binding properties) to compensate for the lack of sigma-1 receptor.
Ligands
Today, ligands are known which have high affinity for the σ1 receptor and possess high binding selectivity over the subtype σ2:- L-687,384L-687,384L-687,384 is a sigma receptor agonist, selective for the σ1 subtype, as well as an NMDA antagonist....
- PRE-084PRE-084PRE-084 is a sigma receptor agonist, selective for the σ1 subtype. It has nootropic and antidepressant actions in animal studies, as well as antitussive and reinforcing effects. PRE-084 increases the expression of GDNF....
: agonist - PD 144418
- 3--[(4-chlorophenyl)methyl]-4-piperidyl]methyl]-1,3-benzoxazol-2-one: very high affinity and subtype selectivity
- 1'-[(4-fluorophenyl)methyl]spiro[1H-isobenzofuran-3,4'-piperidine]
- 1-benzyl-6′-methoxy-6′,7′-dihydrospiro[piperidine-4,4′-thieno[3.2-c]pyran]: putative antagonist, selective against 5-HT1A, 5-HT6, 5-HT7, α1A and α2 adrenergic, and NMDA receptors
- 1'-benzyl-6-methoxy-1-phenyl-spiro[6H-furo[3,4-c]pyrazole-4,4'-piperidine]
- (−)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-1-methylethyl]piperidine
Agents exist that have high σ1 affinity but either lack subtype selectivity or have high affinity at other binding sites, thus being more or less dirty
Dirty drug
A dirty drug is an informal term used in pharmacology to describe drugs that may bind to many different molecular targets or receptors in the body, and so tend to have a wide range of effects and possibly negative side effects...
/multifunctional, like haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
. Furthermore, there is a wide range of agents with an at least moderate σ1 involvement in their binding profile.