Targeting microglia L‐type voltage‐dependent calcium channels for the treatment of central nervous system disorders

Abstract

Calcium (Ca2+) is a ubiquitous mediator of a multitude of cellular functions in the central nervous system (CNS). Intracellular Ca2+ is tightly regulated by cells, including entry via plasma membrane Ca2+ permeable channels. Of specific interest for this review are L‐type voltage‐dependent Ca2+ channels (L‐VDCCs), due to their pleiotropic role in several CNS disorders. Currently, there are numerous approved drugs that target L‐VDCCs, including dihydropyridines. These drugs are safe and effective for the treatment of humans with cardiovascular disease and may also confer neuroprotection. Here, we review the potential of L‐VDCCs as a target for the treatment of CNS disorders with a focus on microglia L‐VDCCs. Microglia, the resident immune cells of the brain, have attracted recent attention for their emerging inflammatory role in several CNS diseases. Intracellular Ca2+ regulates microglia transition from a resting quiescent state to an “activated” immune‐effector state and is thus a valuable target for manipulation of microglia phenotype. We will review the literature on L‐VDCC expression and function in the CNS and on microglia in vitro and in vivo and explore the therapeutic landscape of L‐VDCC‐targeting agents at present and future challenges in the context of Alzheimer's disease, Parkinson's disease, Huntington's disease, neuropsychiatric diseases, and other CNS disorders.

Altered Expression of Ion Channels in White Matter Lesions of Progressive Multiple Sclerosis: What Do We Know About Their Function?

“…Neuronal Ca V 1.2 channels are involved in synaptic modulation, propagation of dendritic Ca 2+ spikes, regulation of glutamate receptor trafficking, CREB phosphorylation, coupling of excitation to nuclear gene transcription, modulation of long-term potentiation, spatial learning, and fear response (Hofmann et al, 2014 ; Hopp, 2021 ). During brain development, spontaneous Ca 2+ transients mediated by Ca V 1.2 channels regulate neurite growth and axonal pathfinding (Huang et al, 2012 ; Kamijo et al, 2018 ).…”

“…Functional expression of Ca V 1.2 channels in microglia is still debated (Hopp, 2021 ). Sequencing data showed no/low CACNA1C expression in microglia (Hammond et al, 2019 ), and no Ca V 1.2 was found in cultured microglia even upon stimulation with TNF-α/IFN-γ (Schampel et al, 2017 ).…”

Upregulation of Neuronal Cylindromatosis Expression is Essential for Electroacupuncture-Mediated Alleviation of Neuroinflammatory Injury by Regulating Microglial Polarization in Rats Subjected to Focal Cerebral Ischemia/Reperfusion

“…[6][7][8] Similar to other tissue-specific resident macrophages, microglia induce an immune response to pathogens, mediate exogenous injury and maintain homeostasis by eliminating agents, apoptotic cells, debris and denatured proteins. 8,9 Interestingly, stimulated neurons activate various signaling pathways, including cytokines and chemokines, and the receptors of these cytokines and chemokines are exclusively expressed by microglia.…”

Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca2+ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders

“…High level of calcium activates several toxic or disadvantageous mechanisms, e.g., activation of nitric oxide synthase (NOS), lipases, proteases, kinases, endonucleases, leading finally to stress, energy crisis and disturbances in synaptic transmission. Calcium is also involved in regulating microglial transition from a "surveying" state to an "active" state [27]. The important role of calcium in regulating gene expression is well known [28], but recent studies demonstrated its involvement also in epigenetic mechanisms and splicing regulation [29][30][31][32].…”