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

Calcium (Ca ) is a ubiquitous mediator of a multitude of cellular functions in the central nervous system (CNS). Intracellular Ca is tightly regulated by cells, including entry via plasma membrane Ca permeable channels. Of specific interest for this review are L-type voltage-dependent Ca 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 Ca 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.