L‐type Ca²⁺ channels in heart and brain

Abstract

L-type calcium channels (Cav1) represent one of the three major classes (Cav1–3) of voltage-gated calcium channels. They were identified as the target of clinically used calcium channel blockers (CCBs; so-called calcium antagonists) and were the first class accessible to biochemical characterization. Four of the 10 known α1 subunits (Cav1.1–Cav1.4) form the pore of L-type calcium channels (LTCCs) and contain the high-affinity drug-binding sites for dihydropyridines and other chemical classes of organic CCBs. In essentially all electrically excitable cells one or more of these LTCC isoforms is expressed, and therefore it is not surprising that many body functions including muscle, brain, endocrine, and sensory function depend on proper LTCC activity. Gene knockouts and inherited human diseases have allowed detailed insight into the physiological and pathophysiological role of these channels. Genome-wide association studies and analysis of human genomes are currently providing even more hints that even small changes of channel expression or activity may be associated with disease, such as psychiatric disease or cardiac arrhythmias. Therefore, it is important to understand the structure–function relationship of LTCC isoforms, their differential contribution to physiological function, as well as their fine-tuning by modulatory cellular processes.

Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channels

“…Different classes of voltage-gated Ca 2+ channels serve a central role for key physiological processes by generating inward Ca 2+ currents in response to changes in membrane potentials in electrically excitable cells [1–3]. Ca 2+ influx through these channels drives not only membrane depolarization but, through Ca 2+ ions as universal second messenger, also regulates a large variety of intracellular Ca 2+ dependent processes.…”

“…Ca 2+ influx through these channels drives not only membrane depolarization but, through Ca 2+ ions as universal second messenger, also regulates a large variety of intracellular Ca 2+ dependent processes. These include muscle contraction, gene transcription, hormone secretion, neurotransmitter release, synaptic excitability and plasticity [1–3]. Their subcellular targeting as well as the dynamics of Ca 2+ entry need to be tightly controlled by accessory subunits, post-translational modification, lipid- and protein interactions, as well as alternative splicing [1,2].…”

“…These include muscle contraction, gene transcription, hormone secretion, neurotransmitter release, synaptic excitability and plasticity [1–3]. Their subcellular targeting as well as the dynamics of Ca 2+ entry need to be tightly controlled by accessory subunits, post-translational modification, lipid- and protein interactions, as well as alternative splicing [1,2]. The occurrence of human channelopathies resulting from even minor changes in Ca 2+ channel activity [4–8] further emphasizes the importance of strictly regulated channel gating and targeting for normal physiological function.…”

Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca2+ channel activators

“…They are expressed in most electrically excitable cells [1][2][3] . Many physiological processes, including muscle, brain, endocrine and sensory function, depend on proper LTCC activity 2 .…”

“…They are predominantly located at postsynaptic somatodendritic locations, are often present in the same neuron 6 and shape shortand long-term adaptations of synaptic function 2,4,6,7 . However, they are functionally distinct and contribute differently to various brain functions, such as emotional and drug-taking behaviours and different types of memory [2][3][4] . Cav1.3 comprises onlyB10% of LTCCs in the brain 8 , but due to its more negative activation voltage range it carries inward current at threshold voltages 9,10 .…”