The sigma1 receptor interacts with N-alkyl amines and endogenous sphingolipids

Ramachandran, Subramaniam; Chu, Uyen B.; Mavlyutov, Timur A.; Pal, Arindam; Pyne, Susan; Ruoho, Arnold E.

doi:10.1016/j.ejphar.2009.03.003

Cited by 80 publications

(88 citation statements)

References 38 publications

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“…It was noted that synthetic long-chain N-alkyl amines interact with the S1R. Based on this observation it was discovered that endogenous long-chain sphingoid bases such as D-erythro sphingosine, which conform to the S1R pharmacophore motif of a long N-alkyl chain with a nitrogen atom containing unshared electrons, interact with the S1R (Ramachandran et al, 2009;Chu et al, 2011Chu et al, , 2013. The endogenous long-chain sphingoid bases D-erythro-sphingosine, L-threo-sphingosine, dihydrosphingosine (sphinganine), and N,Nʹ-dimethyl sphingosine inhibited […”

Section: S1r Interactions With Lipidsmentioning

confidence: 99%

Biochemical Pharmacology of the Sigma-1 Receptor

2015

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The sigma-1 receptor (S1R) is a 223 amino acid two transmembrane (TM) pass protein. It is a non-ATP-binding nonglycosylated ligand-regulated molecular chaperone of unknown three-dimensional structure. The S1R is resident to eukaryotic mitochondrial-associated endoplasmic reticulum and plasma membranes with broad functions that regulate cellular calcium homeostasis and reduce oxidative stress. Several multitasking functions of the S1R are underwritten by chaperone-mediated direct (and indirect) interactions with ion channels, G-protein coupled receptors and cell-signaling molecules involved in the regulation of cell growth. The S1R is a promising drug target for the treatment of several neurodegenerative diseases related to cellular stress. In vitro and in vivo functional and molecular characteristics of the S1R and its interactions with endogenous and synthetic small molecules have been discovered by the use of pharmacologic, biochemical, biophysical, and molecular biology approaches. The S1R exists in monomer, dimer, tetramer, hexamer/octamer, and higher oligomeric forms that may be important determinants in defining the pharmacology and mechanism(s) of action of the S1R. A canonical GXXXG in putative TM2 is important for S1R oligomerization. The ligand-binding regions of S1R have been identified and include portions of TM2 and the TM proximal regions of the C terminus. Some client protein chaperone functions and interactions with the cochaperone 78-kDa glucose-regulated protein (binding immunoglobulin protein) involve the C terminus. Based on its biochemical features and mechanisms of chaperone action the possibility that the S1R is a member of the small heat shock protein family is discussed.

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Section: S1r Interactions With Lipidsmentioning

confidence: 99%

Biochemical Pharmacology of the Sigma-1 Receptor

2015

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“…Those data suggested the possibility that the Sig-1R binds myristic acid and serves to increase the myristoylation of p35 and facilitate the p35 anchoring to the membrane. This idea is not implausible because lipids have been reported to bind to Sig-1Rs (34)(35)(36). We therefore examined next whether myristic acid binds to Sig-1Rs.…”

Section: Sig-1r Controls P35 Degradation Mainly Through the Proteasomalmentioning

confidence: 99%

“…Specifically, lipids are closely related to neurodegeneration (52,53). Although Sig-1Rs bind to certain lipids (34)(35)(36) and have been shown to partake in lipid biosynthesis (54,55), the specific physiological role arising from the Sig-1R-lipid interaction remains unknown. Thus, to our knowledge, our present finding constitutes the first report on the physiological consequence of the Sig-1R-lipid interaction.…”

Section: Sig-1r Controls P35 Degradation Mainly Through the Proteasomalmentioning

confidence: 99%

“…We decided to examine here if a potential relation between Sig-1R and cdk5 may exist. In particular, the Sig-1R has been shown to bind cholesterol as well as sphingolipids, ceramides, progesterone, and other endogenous lipids (26,(33)(34)(35)(36). Thus, because of this lipid-binding property of Sig-1Rs and because the myristoylation of p35 contributes to its degradation, we set forth to examine if the action of Sig-1Rs in tauopathy, if any, may relate to Sig-1R's potential ability to bind myristic acid.…”

Section: Significancementioning

confidence: 99%

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Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

Tsai

Pokrass

Klauer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Dysregulation of cyclin-dependent kinase 5 (cdk5) per relative concentrations of its activators p35 and p25 is implicated in neurodegenerative diseases. P35 has a short t ½ and undergoes rapid proteasomal degradation in its membrane-bound myristoylated form. P35 is converted by calpain to p25, which, along with an extended t ½ , promotes aberrant activation of cdk5 and causes abnormal hyperphosphorylation of tau, thus leading to the formation of neurofibrillary tangles. The sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperone that is implicated in neuronal survival. However, the specific role of the Sig-1R in neurodegeneration is unclear. Here we found that Sig-1Rs regulate proper tau phosphorylation and axon extension by promoting p35 turnover through the receptor's interaction with myristic acid. In Sig-1R-KO neurons, a greater accumulation of p35 is seen, which results from neither elevated transcription of p35 nor disrupted calpain activity, but rather to the slower degradation of p35. In contrast, Sig-1R overexpression causes a decrease of p35. Sig-1R-KO neurons exhibit shorter axons with lower densities. Myristic acid is found here to bind Sig-1R as an agonist that causes the dissociation of Sig-1R from its cognate partner binding immunoglobulin protein. Remarkably, treatment of Sig-1R-KO neurons with exogenous myristic acid mitigates p35 accumulation, diminishes tau phosphorylation, and restores axon elongation. Our results define the involvement of Sig-1Rs in neurodegeneration and provide a mechanistic explanation that Sig-1Rs help maintain proper tau phosphorylation by potentially carrying and providing myristic acid to p35 for enhanced p35 degradation to circumvent the formation of overreactive cdk5/p25.A xons are structurally and functionally distinct protrusions of neurons that modulate neurotransmitter release and neural function. Malfunction of axonal maintenance, regeneration, and target recognition contribute to CNS disorders such as Alzheimer's disease (AD), Parkinson's disease, stroke, and spinal cord injuries (1-3). Cyclin-dependent kinase (Cdk) 5 activities within the axon play a significant role in the cytoskeletal dynamics of microtubules and actin neurofilaments (NFs), which determine axonal path and length. Specifically, cdk5 active complexes phosphorylate proteins that contribute to the stabilization or destabilization of microtubules, formation of neurofibrillary tangles, and axonal pathfinding (4-6).Cdk5 is a ubiquitously expressed enzyme; however, its activator, p35, is almost exclusively expressed in neurons (7,8). Cdk5 signaling supports neurite projection and proper neuronal migration (9-11). Dysregulation of cdk5 activity leads to hyperphosphorylation of several substrates, including NF proteins and tau, which causes the formation of neurofibrillary tangles (6, 12). Although the kinetics of cdk5 activity when in complex with p35 or p25 are the same, cdk5/p25 complexes are proposed to be responsible for neurodegenerative pathophysiology because of their longer duration o...

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“…Neurosteroids, i.e. steroid hormones which are synthesized within the brain itself [84,95,101,143], and sphingolipids [134] interact with sigma-1 sites which are now considered as ligand-regulated molecular chaperones modulating the activity of voltage-regulated and ligand-gated ion channels [98], intracellular calcium signaling [39], and the release of various neurotransmitters including acetylcholine [45,58,63] and glutamate [107]. Occupancy of sigma-1 receptors by agonists causes translocation of the receptor protein from the endoplasmatic reticulum to the cell membrane where the receptor can regulate ion channels and neurotransmitter release [36,39] (Fig.…”

Section: Introductionmentioning

confidence: 99%

The cholinergic system, sigma-1 receptors and cognition

Waarde

Ramakrishnan

Rybczynska

et al. 2011

Behavioural Brain Research

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a b s t r a c tThis article provides an overview of present knowledge regarding the relationship between the cholinergic system and sigma-1 receptors, and discusses potential applications of sigma-1 receptor agonists in the treatment of memory deficits and cognitive disorders. Sigma-1 receptors, initially considered as a subtype of the opioid family, are unique ligand-regulated molecular chaperones in the endoplasmatic reticulum playing a modulatory role in intracellular calcium signaling and in the activity of several neurotransmitter systems, particularly the cholinergic and glutamatergic pathways. Several central nervous system (CNS) drugs show high to moderate affinities for sigma-1 receptors, including acetylcholinesterase inhibitors (donepezil), antipsychotics (haloperidol, rimcazole), selective serotonin reuptake inhibitors (fluvoxamine, sertraline) and monoamine oxidase inhibitors (clorgyline). These compounds can influence cognitive functions both via their primary targets and by activating sigma-1 receptors in the CNS. Sigma-1 agonists show powerful anti-amnesic and neuroprotective effects in a large variety of animal models of cognitive dysfunction involving, among others (i) pharmacologic target blockade (with muscarinic or NMDA receptor antagonists or p-chloroamphetamine); (ii) selective lesioning of cholinergic neurons; (iii) CNS administration of ␤-amyloid peptides; (iv) aging-induced memory loss, both in normal and senescentaccelerated rodents; (v) neurodegeneration induced by toxic compounds (CO, trimethyltin, cocaine), and (vi) prenatal restraint stress.

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The sigma1 receptor interacts with N-alkyl amines and endogenous sphingolipids

Cited by 80 publications

References 38 publications

Biochemical Pharmacology of the Sigma-1 Receptor

Biochemical Pharmacology of the Sigma-1 Receptor

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

The cholinergic system, sigma-1 receptors and cognition

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