The Roles of Intracellular Chaperone Proteins, Sigma Receptors, in Parkinson’s Disease (PD) and Major Depressive Disorder (MDD)

Abstract

Sigma receptors, including Sigma-1 receptors and Sigma-2 receptors, are highly expressed in the CNS. They are intracellular chaperone proteins. Sigma-1 receptors localize mainly at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM). Upon stimulation, they translocate from MAM to plasma membrane (PM) and nucleus, where they interact with many proteins and ion channels. Sigma-1 receptor could interact with itself to form oligomers, its oligomerization states affect its ability to interact with client proteins including ion channels and BiP. Sigma-1 receptor shows high affinity for many unrelated and structurally diverse ligands, but the mechanism for this diverse drug receptor interaction remains unknown. Sigma-1 receptors also directly bind many proteins including G protein-coupled receptors (GPCRs) and ion channels. In recent years, significant progress has been made in our understanding of roles of the Sigma-1 receptors in normal and pathological conditions, but more studies are still required for the Sigma-2 receptors. The physiological roles of Sigma-1 receptors in the CNS are discussed. They can modulate the activity of many ion channels including voltage-dependent ion channels including Ca 2+ , Na + , K + channels and NMDAR, thus affecting neuronal excitability and synaptic activity. They are also involved in synaptic plasticity and learning and memory. Moreover, the activation of Sigma receptors protects neurons from death via the modulation of ER stress, neuroinflammation, and Ca 2+ homeostasis. Evidences about the involvement of Sigma-1 receptors in Parkinson’s disease (PD) and Major Depressive Disorder (MDD) are also presented, indicating Sigma-1 receptors might be promising targets for pharmacologically treating PD and MDD.

Dexmedetomidine inhibits neuronal apoptosis by inducing Sigma-1 receptor signaling in cerebral ischemia-reperfusion injury

“…Sig-1R has been reported to regulate retinal cell pressure [20], to inhibit the neuropathic pain caused by partial sciatic nerve transection in mice [33], to lessen the severity of depressive disorder and to have neurorestorative effects in Parkinson's disease [34]. Sig-1R exerts neuroprotective effects by regulating Ca 2+ homeostasis and preventing glutamate toxicity and neuroinflammation [34]. We found that Sig-1R expression on the ER was significantly upregulated in the early stage of CIRI, and decreased with increasing reperfusion times, consistent with the expression trend of GRP78.…”

Activation of astrocytic sigma‐1 receptor exerts antidepressant‐like effect via facilitating CD38‐driven mitochondria transfer

“…The action of Sig-1R in neurons has been revealed to affect neuronal excitability and survival (Yang, Wang, & Sun, 2019). Furthermore, the activation of Sig-1R enhances the neural axonal outgrowth and neurogenesis while knockdown of Sig-1R inhibits hippocampal dendritic spine and synapse formation (Aleksandrova, Phillips, & Wang, 2017;Fukunaga & Moriguchi, 2017;Tsai et al, 2009).…”

Chaperone Sigma1R mediates the neuroprotective action of afobazole in the 6-OHDA model of Parkinson’s disease

“…Sigma1Rs and sigma-2 receptors are different proteins encoded by diverse genes 9,58,59 . The interconnection of these two proteins in physiological processes is poorly understood 60–62 . However, the sigma-2 receptor may be a part of the protective pathway that is triggered by the interaction of the Sigma1R chaperone with afobazole.…”