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

J Neurosci Res. 2021 Jan;99(1):141-162. doi: 10.1002/jnr.24585. Epub 2020 Jan 29.

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.

Keywords: Alzheimer's disease; CACNA1C; CACNA1D; Cav1.2; Cav1.3; Huntington's disease; L-type voltage-dependent calcium channels; Parkinson's disease; aging; bipolar disorder; calcium; depression; microglia; neuroinflammation; neuropsychiatric diseases; schizophrenia.

Publication types

  • Review

MeSH terms

  • Animals
  • Calcium Channels, L-Type / metabolism*
  • Central Nervous System Diseases / metabolism*
  • Humans
  • Microglia / metabolism*

Substances

  • Calcium Channels, L-Type