https://www.cell.com/cell/pdf/S0092-8674(09)01243-4.pdf

Cellular and Molecular Mechanisms of Pain

Persistent postsurgical pain: risk factors and prevention

Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed "resting microglia." Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the "activated microglial cell." This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

Physiology of Microglia

In electrically nonexcitable cells, Ca2+ influx is essential for regulating a host of kinetically distinct processes involving exocytosis, enzyme control, gene regulation, cell growth and prolifera...

Store-operated calcium channels.

The family of voltage-gated sodium channels initiates action potentials in all types of excitable cells. Nine members of the voltage-gated sodium channel family have been characterized in mammals, and a 10th member has been recognized as a related protein. These distinct sodium channels have similar structural and functional properties, but they initiate action potentials in different cell types and have distinct regulatory and pharmacological properties. This article presents the molecular relationships and physiological roles of these sodium channel proteins and provides comprehensive information on their molecular, genetic, physiological, and pharmacological properties.

https://pharmrev.aspetjournals.org/content/pharmrev/57/4/411.full.pdf

International Union of Pharmacology. XLVIII. Nomenclature and Structure-Function Relationships of Voltage-Gated Calcium Channels

Microglia are important mediators of neuroinflammation that underlies neuropathic pain. However, the molecular checkpoints controlling microglial reactivity are not well-understood. We investigated the role of Orai1 channels for microglia-mediated neuroinflammation following nerve injury and find that deletion of Orai1 in microglia attenuates Ca2+ signaling and the production of inflammatory cytokines by proalgesic agonists. Conditional deletion of Orai1 attenuated microglia proliferation in the dorsal horn, spinal cytokines levels, and potentiation of excitatory neurotransmission following peripheral nerve injury. These cellular effects were accompanied by mitigation of pain hyperalgesia in Orai1 knockout mice. A small-molecule Orai1 inhibitor, CM4620, similarly mitigated allodynia in male mice. Surprisingly, these protective effects were not seen in female mice, revealing striking sexual dimorphism in Orai1 regulation of microglial reactivity and hyperalgesia. These findings indicate that Orai1 channels are key regulators of the sexually dimorphic role of microglia for the neuroinflammation that underlies neuropathic pain.

https://doi.org/10.1101/2022.09.02.506250

Regulation of neuropathic pain by microglial Orai1 channels

Relative contributions of G protein, channel, and receptor to voltage-dependent inhibition of neuronal N-type and P/Q-type calcium channels in HEK 293 cell lines

Methods are provided for identifying agents that modulate intracellular calcium. Also provided are methods of modulating calcium within cells and methods of identifying proteins involved in modulating intracellular calcium.

Composition comprising a cell comprising a STIM1 protein and an agent that modulates intracellular calcium and methods of use

353 An Open-Label, Dose-Response Study of CM4620-Injectable Emulsion in Emergency Department Patients With Acute Pancreatitis

Provided herein are pharmaceutical compositions, such as emulsions and nanosuspensions, comprising a CRAC channel inhibitor. Also provided herein are methods of treating pancreatitis, viral infections, stroke, traumatic brain injury, fibrosis, inflammation, and autoimmune diseases by administering such pharmaceutical compositions.

Kenneth A. Stauderman

Papers

Regulation of neuropathic pain by microglial Orai1 channels

Relative contributions of G protein, channel, and receptor to voltage-dependent inhibition of neuronal N-type and P/Q-type calcium channels in HEK 293 cell lines

Composition comprising a cell comprising a STIM1 protein and an agent that modulates intracellular calcium and methods of use

353 An Open-Label, Dose-Response Study of CM4620-Injectable Emulsion in Emergency Department Patients With Acute Pancreatitis

Crac channel inhibitor compositions