The Sigma-1 Receptor-A Therapeutic Target for the Treatment of ALS?
The membrane bound 223 amino acid Sigma-1 Receptor (S1R) serves as a molecular chaperone and functional regulator of many signaling proteins. Spinal cord motor neuron activation occurs, in part, via large ventral horn cholinergic synapses called C-boutons/C-terminals. Chronic excitation of motor neurons and alterations in C-terminals has been associated with Amyotrophic Lateral Sclerosis (ALS ). The S1R has an important role in regulating motor neuron function. High levels of the S1R are localized in postsynaptic endoplasmic reticulum (ER) subsurface cisternae within 10-20 nm of the plasma membrane that contain muscarinic type 2 acetylcholine receptors (M2AChR), calcium activated potassium channels (Kv2.1) and slow potassium (SK) channels. An increase in action potentials in the S1R KO mouse motor neurons indicates a critical role for the S1R as a "brake" on motor neuron function possibly via calcium dependent hyperpolarization mechanisms involving the aforementioned potassium channels. The longevity of SOD-1/S1R KO ALS mice is significantly reduced compared to SOD-1/WT ALS controls. The S1R colocalizes in C-terminals with Indole(ethyl)amine-N-methyl transferase (INMT ), the enzyme that produces the S1R agonist , N,N'- dimethyltryptamine (DMT). INMT methylation can additionally neutralize endogenous toxic sulfur and selenium derivatives thus providing functional synergism with DMT to reduce oxidative stress in motor neurons . Small molecule activation of the S1R and INMT thus provides a possible therapeutic strategy to treat ALS .
Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
Timur A
TA
Mavlyutov
Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
Erin M
EM
Baker
Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
Tasher M
TM
Losenegger
Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
Jaimie R
JR
Kim
Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
Brian
B
Torres
Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
Miles L
ML
Epstein
Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA. aeruoho@wisc.edu.
Arnold E
AE
Ruoho
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D000097605:Sigma-1 Receptor
D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
ALS; C-terminals; Dorsal root ganglion; INMT; Motor neuron; Sigma-1 receptor