Sigma-1 receptor explained

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]

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.

An endogenous ligand for the σ1 receptor has yet to be conclusively identified, but tryptaminergic trace amines and neuroactive steroids have been found to activate the receptor.[7] Especially progesterone, but also testosterone, pregnenolone sulfate, N,N-Dimethyltryptamine (DMT) and dehydroepiandrosterone sulfate (DHEA-S) bind to the σ1 receptor.[8]

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).[9] The opioid classification was eventually dropped however resulting from it not possessing the canonical opioid G-protein coupled receptor structure and the receptor was later referred to as simply the σ1 receptor. It was found to have affinity for the (+)-stereoisomers of several benzomorphans (e.g., (+)-pentazocine and (+)-cyclazocine), as well as various structurally and pharmacologically distinct psychoactive chemicals such as haloperidol and cocaine, and neuroactive steroids like progesterone.[10] Pharmacological studies with σ1 agonists often follow a bell-shaped dose-response curve. Thus care should be taken when designing experiments and choosing doses of ligands.

Structure

The mammalian σ1 receptor is an integral membrane protein with 223 amino acids.[11] It shows no homology to other mammalian proteins but strikingly shares 30% sequence identity and 69% similarity with the ERG2 gene product of yeast, which is a C8-C7 sterol isomerase in the ergosterol biosynthetic pathway. Hydropathy analysis of the σ1 receptor indicates three hydrophobic regions.[12] A crystal structure of the σ1 receptor was published in 2016.[13]

Functions

A variety of specific physiological functions have been attributed to the σ1 receptor. Chief among these are modulation of Ca2+ release, modulation of cardiac myocyte contractility, and inhibition of voltage gated K+ channels.[14] The reasons for these effects are not well understood, even though σ1 receptors have been linked circumstantially to a wide variety of signal transduction pathways. Links between σ1 receptors and G-proteins have been suggested such as σ1 receptor antagonists showing GTP-sensitive high-affinity binding;[15] there is also, however, some evidence against a G-protein coupled hypothesis.[16] The σ1 receptor has been shown to appear in a complex with voltage gated K+ channels (Kv1.4 and Kv1.5), leading to the idea that σ1 receptors are auxiliary subunits.[17] σ1 receptors apparently co-localize with IP3 receptors on the endoplasmic reticulum[18] where they may be involved in preventing endoplasmic reticulum stress in neurodegenerative diseases.[19] Also, σ1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes.[20] The wide scope and effect of ligand binding on σ1 receptors has led some to believe that σ1 receptors are intracellular signal transduction amplifiers.

Recently, σ1R has been implicated in autophagosome formation [21] and maturation.[22] Autophagy is a broad homeostatic, metabolic, cytoplasmic quality control, and metabolic process affecting many functions in the cell.[23] σ1R is targeted by the nsp6 protein of SARS-CoV-2[24] to inhibit autophagosome formation as a process competing with the coronavirus for cellular endomembranes that the virus needs for its own replication. This along with the observed beneficial effects of sigma-1 receptor agonist and SSRI fluvoxamine in patients with SARS-COV-2 infection[25] has led to the hypothesis that the sigma-1 receptor could be a target for the treatment of SARS-COV-2.[26]

There has been much interest in the sigma-1 receptor and its role in age-related neurodegenerative diseases such as Alzheimer's disease. During healthy ageing, the density of sigma-1 receptors has been to increase. However, in diseases such as Alzheimer's disease, there appears to be a reduction in sigma-1 receptor expression. It has been suggested that targeting the sigma-1 receptor along with other receptors could increase neuron survival and function in neurodegenerative disease.[27] The activation of autophagy has also been suggested as a downstream mechanism linked to sigma-1 receptor activation.[28]

Knockout mice

σ1 receptor knockout mice were created in 2003 to study the effects of endogenous DMT. Strangely, the mice demonstrated no overt phenotype.[29] As expected, however, they did lack locomotor response to the σ ligand (+)-SKF-10,047 and displayed reduced response to formalin induced pain. Speculation has focused on the ability of other receptors in the σ family (e.g., σ2, with similar binding properties) to compensate for the lack of σ1 receptor.

Clinical significance

Mutations in the SIGMAR1 gene have been associated with distal spinal muscular atrophy type 2.[30]

Ligands

The following ligands have high affinity for the σ1 receptor and possess high binding selectivity over the subtype σ2:[31]

Agonists:

Antagonists:

Positive allosteric modulators (PAMs):

Uncategorized:

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.[42] [43] [44]

See also

Notes and References

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  2. Kekuda R, Prasad PD, Fei YJ, Leibach FH, Ganapathy V . Cloning and functional expression of the human type 1 sigma receptor (hSigmaR1) . Biochemical and Biophysical Research Communications . 229 . 2 . 553–558 . December 1996 . 8954936 . 10.1006/bbrc.1996.1842 .
  3. Prasad PD, Li HW, Fei YJ, Ganapathy ME, Fujita T, Plumley LH, Yang-Feng TL, Leibach FH, Ganapathy V . 6 . Exon-intron structure, analysis of promoter region, and chromosomal localization of the human type 1 sigma receptor gene . Journal of Neurochemistry . 70 . 2 . 443–451 . February 1998 . 9453537 . 10.1046/j.1471-4159.1998.70020443.x . 22305479 . free .
  4. Weissman AD, Su TP, Hedreen JC, London ED . Sigma receptors in post-mortem human brains . The Journal of Pharmacology and Experimental Therapeutics . 247 . 1 . 29–33 . October 1988 . 2845055 .
  5. Guitart X, Codony X, Monroy X . Sigma receptors: biology and therapeutic potential . Psychopharmacology . 174 . 3 . 301–319 . July 2004 . 15197533 . 10.1007/s00213-004-1920-9 . 23606712 .
  6. Zhang H, Cuevas J . sigma Receptor activation blocks potassium channels and depresses neuroexcitability in rat intracardiac neurons . The Journal of Pharmacology and Experimental Therapeutics . 313 . 3 . 1387–1396 . June 2005 . 15764734 . 10.1124/jpet.105.084152 . 9704436 .
  7. Fontanilla D, Johannessen M, Hajipour AR, Cozzi NV, Jackson MB, Ruoho AE . The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator . Science . 323 . 5916 . 934–937 . February 2009 . 19213917 . 2947205 . 10.1126/science.1166127 . 2009Sci...323..934F .
  8. Hayashi T, Su TP . Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders . CNS Drugs . 18 . 5 . 269–284 . 2004 . 15089113 . 10.2165/00023210-200418050-00001 . 72726251 .
  9. Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE . The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog . The Journal of Pharmacology and Experimental Therapeutics . 197 . 3 . 517–532 . June 1976 . 945347 .
  10. Su TP, Hayashi T . Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction . Current Medicinal Chemistry . 10 . 20 . 2073–2080 . October 2003 . 12871086 . 10.2174/0929867033456783 .
  11. Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kempner E, Glossmann H . Purification, molecular cloning, and expression of the mammalian sigma1-binding site . Proceedings of the National Academy of Sciences of the United States of America . 93 . 15 . 8072–8077 . July 1996 . 8755605 . 38877 . 10.1073/pnas.93.15.8072 . free . 1996PNAS...93.8072H .
  12. Moebius FF, Striessnig J, Glossmann H . The mysteries of sigma receptors: new family members reveal a role in cholesterol synthesis . Trends in Pharmacological Sciences . 18 . 3 . 67–70 . March 1997 . 9133773 . 10.1016/s0165-6147(96)01037-1 .
  13. Schmidt HR, Zheng S, Gurpinar E, Koehl A, Manglik A, Kruse AC . Crystal structure of the human σ1 receptor . Nature . 532 . 7600 . 527–530 . April 2016 . 27042935 . 5550834 . 10.1038/nature17391 . 2016Natur.532..527S .
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  15. Brimson JM, Brown CA, Safrany ST . Antagonists show GTP-sensitive high-affinity binding to the sigma-1 receptor . British Journal of Pharmacology . 164 . 2b . 772–780 . September 2011 . 21486275 . 3188898 . 10.1111/j.1476-5381.2011.01417.x .
  16. Hong W, Werling LL . Evidence that the sigma(1) receptor is not directly coupled to G proteins . European Journal of Pharmacology . 408 . 2 . 117–125 . November 2000 . 11080517 . 10.1016/S0014-2999(00)00774-3 .
  17. Lupardus PJ, Wilke RA, Aydar E, Palmer CP, Chen Y, Ruoho AE, Jackson MB . Membrane-delimited coupling between sigma receptors and K+ channels in rat neurohypophysial terminals requires neither G-protein nor ATP . The Journal of Physiology . 526 Pt 3 . 3 . 527–539 . August 2000 . 10922005 . 2270035 . 10.1111/j.1469-7793.2000.00527.x .
  18. Hayashi T, Su TP . Regulating ankyrin dynamics: Roles of sigma-1 receptors . Proceedings of the National Academy of Sciences of the United States of America . 98 . 2 . 491–496 . January 2001 . 11149946 . 14614 . 10.1073/pnas.021413698 . free .
  19. Brimson JM, Safrany ST, Qassam H, Tencomnao T . Dipentylammonium Binds to the Sigma-1 Receptor and Protects Against Glutamate Toxicity, Attenuates Dopamine Toxicity and Potentiates Neurite Outgrowth in Various Cultured Cell Lines . Neurotoxicity Research . 34 . 2 . 263–272 . August 2018 . 29589276 . 10.1007/s12640-018-9883-5 . 4378593 .
  20. Hayashi T, Su TP . Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation . Proceedings of the National Academy of Sciences of the United States of America . 101 . 41 . 14949–14954 . October 2004 . 15466698 . 522002 . 10.1073/pnas.0402890101 . free . 2004PNAS..10114949H .
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  22. Yang H, Shen H, Li J, Guo LW . SIGMAR1/Sigma-1 receptor ablation impairs autophagosome clearance . Autophagy . 15 . 9 . 1539–1557 . September 2019 . 30871407 . 6693456 . 10.1080/15548627.2019.1586248 .
  23. Levine B, Kroemer G . Biological Functions of Autophagy Genes: A Disease Perspective . Cell . 176 . 1–2 . 11–42 . January 2019 . 30633901 . 6347410 . 10.1016/j.cell.2018.09.048 .
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