The role of L-type voltage-gated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain functions

Berger, Stefan M., and Dusan Bartsch. "The role of L-type voltage-gated calcium channels Cav1. 2 and Cav1. 3 in normal and pathological brain function." Cell and tissue research 357.2 (2014): 463-476. There are multiple types of voltage-gated calcium channels (VGCCs) including L-type, T-type, P/Q-type, R-type, and N-type that are defined by their pharmacological responses. Each channel is made up of five subunits, with the main pore forming subunit being alpha1. For this discussion I will mainly be focusing on the L-type calcium channels(1.1-1.4) which are believed to be the channels that allow manganese entry into a depolarized cell when using manganese enhanced MRI. More specifically, I will be focusing on 1.2 and 1.3 which are expressed by in large in the body compared to the more restricted 1.1 and 1.4. Cav1.2 and Cav1.3 can be found on multiple organs in the periphery including the hear, smooth muscle, pancreases, and adrenal glands, but most importantly for my studies, both of these channels are also expressed on neurons in the brain. With some cells expressing both 1.2 and 1.3, leading to the hypothesis that each channel may have its own specific function and importance. Some studies using radioreceptor assays have suggested that 89% of all Cav isoforms in the brain are 1.2, where as only 11% are 1.3. However, other studies utilizing western blotting have stated that within neurons in the hippocampus, cerebral cortex, and cerebellum 1.2 and 1.3 isoforms are equally abundant. As for location within a cell, it appears 1.2 are mostly found on the post synaptic dendrites, compared to the 1.3 which is most dense around the cell body. Electrophysiologically, 1.3 isoform channels are activated more rapidly and in more hyperpolarized membranes. They are also inactivated with a slower current than 1.2 isoforms. In both channels calmodulin acts as an imperative calcium sensor that 1) initiates the inactivation of the calcium channel preventing intracellular calcium toxicity 2) causes phosphorylation of the channel which increases the probability of an open state during repeated or prolonged activation and 3) enables the expression of calcium dependent genes within the cell. Unfortunately, there still is not a well established antibody for the isoform 1.3 so these studies may be less reliable then more recent studies being undertaken using Cre recombinase knockout mice. Using genetically modified mice, pharmacological experiments have showed that LTCCs play a role in synaptic plasticity involving learning and memory. Interestingly, injections of LTCC antagonists into the hippocampus have shown increases in acquisition and retention of spatial reference and working memory. Correspondingly, chronic injections into older animals has shown prevention of age-related hippocampal-dependent memory loss. It is believed this change is linked to the loss of NMDA-receptor-independent form of late long-term potentiation. Related, it has also been shown using LTCC antagonist injections into the amygdala that blocking LTCC also blocks the formation of fear memories. Finally, other studies have shown a link between LTCC's and the modulation of the mesoccumbal dopamine signaling pathway, which plays a major role in the reward system and addiction. Compared to animal studies, few human studies have been done analyzing LTCCs. However, in the past few years the hypothesis that LTCC's play an important role in psychiatric diseases is becoming more and more accepted. Stemming from patients with Timothy Syndrome, upregulated LTCC activation leads to the upregulation of tyrosine hydroxylase expression, causing increased concentrations of norepinephrine and dopamine. They have also shown that stimulation of TS-mutated calcium channels 1.2 cells led to dendritic retraction. Since the GWA the CACNA1C gene, associated with the alpha1 subunit on Cav1.2, was identified as a common risk factor allele for bipolar disorder, schizophrenia, and major depression. As for physiological defects in the isoform 1.3, recent studies are showing Cav1.3-mediated vulnerability of the dopaminergic neurons affected by Parkinson's disease. Specifically, increases in calcium entry increases alpha-synuclein aggregates present in Parkinson's disease. Conclusively, very few studies have been done examining the role of VLCC's in normal human cognition up to date. I think studies examining the role of L-type calcium channel activity within the RVLM would be interesting, and may shed light on differences in neuroplasticity between sedentary and physically active animals. ~JI