Sigma-1 and Sigma-2 Chaperone-Receptors for Therapeutic Targets

Abstract Title: Sigma-1 and Sigma-2 Chaperone-Receptors for Therapeutic Targets

Background:

While there is important on-going research into sigma receptors (SR), these efforts remain surprisingly limited. For instance, from 1992 to 2017, only 1,102 peer-reviewed articles on sigma receptors were published and only 247 authors have five or more publications. The majority of articles came from the United States, Germany, and Japan. From a cluster analysis of these articles, it was found that the main focus was on addiction (substance use disorders), psychiatric diseases, neurodegenerative disorders, and pain, although these do not represent the full therapeutic potential of these receptors. Sigma receptors are involved in lipid metabolism, lipid transport, gene transcription, modulation of voltage-gated ion channels (sodium, potassium, and calcium), regulation of non-voltage-gated ion channels, intracellular calcium homeostasis, control of oxidative stress, and the regulation of cellular electrical activity, and likely additional functions.  The chaperone nature of SR proteins allows and accounts for the diversity of their therapeutic potential.

Purpose/Objectives:

The objective of this presentation is to summarize the results of a literature search directed at finding data or speculation relevant to the known or postulated potential therapeutic utility of SR ligands.  The intent was the creation of a short narrative review of the current understanding of sigma receptors and how the evolving elucidation of these protein chaperones may pair with important therapeutic drug targets.

Method:

PubMed and Google Scholar were searched using the keywords “sigma receptor,” “sigma-1 receptor”, and “sigma-2 receptor” for publications in the English language.  The references therein of some of the articles were also searched for additional publications. The goal was to create the basis for a succinct narrative review of a complex and rapidly evolving topic.

Results:

A significant and diverse number of publications implicating or suggestive of a therapeutic role for SR (SR-1 and/or SR-2) ligands (agonist and/or antagonist) was identified.  The therapeutic targets include, (in alphabetical order): addictions (substance use disorders, SUD), Aging, Alzheimer’s disease, Amnesia, Amyloid lateral sclerosis (ALS), Cancer, Cardiovascular disease, Chemotherapy-induced peripheral neuropathy, COVID infection, Depression and Anxiety, Neuropathy, Pain, Parkinson’s disease, Retinal disease, Schizophrenia, and Stroke.  A short summary of the connections or evidence for the putative therapeutic potential is presented for each of the listed therapeutic targets.

Conclusions: Addictions (SUD): Chronic exposure results in neural-network dysregulation (including protein misfolding) that might be corrected by SR chaperones; Aging: Proper protein folding/maintenance may counter declining physiological processes; Alzheimer’s Disease: SR-1 agonists are neuroprotective; SR-2 antagonists inhibit neuronal ß-amyloid accumulation; Amnesia: SR-1 agonists potentiate neuronal firing and increase acetylcholine levels in hippocampus and cerebral cortex; Amyloid Lateral Sclerosis (ALS): A mutation in SR-1 might be associated with juvenile ALS; Cancer: Tumor cells overexpress SR-2; SR-2 ligands may induce cytotoxicity in cancer cells; Cardiovascular Diseases: During oxidative stress to cardiomyocytes, SR-1 can be restorative; Chemotherapy-Induced Peripheral Neuropathy: In animal models, SR-1 antagonists inhibit chemotherapy-induced neuropathic pain; COVID Infection: Coronaviruses replicate in the endoplasmic reticulum, so SR chaperones might be beneficial; Depression and Anxiety: Dysfunctions in neurotransmitter systems are involved, so SR chaperones may be adjuvant treatments; Neuropathy: SR-1 antagonism inhibits peripheral diabetic neuropathy in rats; Pain: The combination with other analgesic mechanisms are currently being explored, particularly for neuropathic pain; Parkinson's Disease: SR-2 antagonists inhibit alpha-synuclein oligomer-trafficking deficits; Retinal Disease: SR-1 plays a major role in regulating retinal cellular stress; Schizophrenia: SR-1 regulates neurotransmitter systems, thought aberrant in schizophrenia; Stroke: SR chaperones might correct/prevent misfolded proteins that inhibit recovery.

References: 1. Pergolizzi et al. (2023) Cureus 15(3):e35756
2. Schmidt 92019) TiPS 40:636-54