SYMPOSIUM 2: The psychopharmacology of emerging calcium channel targets

Calcium ions (Ca2+) are universal intracellular messengers and, through selectively permeable calcium channels, can mediate and drive many important physiological processes. However, excessive calcium channel activation can lead to excitotoxicity within cells. Thus, it is imperative that the opening of these channels is well and precisely regulated. Altered calcium function has become of recent interest within the field of psychopharmacology and Professor Annette Dolphin from UCL begins Symposium 2 of the BAP summer meeting 2017 reviewing the involvement of voltage gated calcium channels (VGCC) in normal neuronal function and dysfunction.

The 1 subunit is a necessary unit for channel function as it forms the channel pore. This subunit determines the kinetics and conductance of VGCCs, though these parameters are also modulated by the associated and 2 subunits. There are 10 different forms of the 1 subunit in mammals all encoded by CACNA1 genes.

Professor Dolphin goes on to outline the some of the areas in which VGCCs are distributed and present. For instance, Cav1.2 are present on dendrites and have postsynaptic roles. Mutation of the CACNA1C gene that encodes for Cav1.2 results in Timothy’s syndrome. Cav1.2 channels are also present in the heart along with Cav1.3 channels and are important targets of dihydropyridine calcium channel blockers. Contrastingly, N-type Cav2.2 channels are present in dorsal root ganglia neurones and in neuropathic pain the 2 subunits of these channels have been found to be upregulated. It becomes apparent that there is a wide distribution of calcium channels within the body and that they already are currently being exploited as therapeutic targets for various disorders.

Professor Andrea Cipriani from Oxford goes on to review previous studies on L-type calcium channel (LTCC) antagonists in bipolar disorder in the hopes that improvements will be made regarding their selectivity, tolerability and efficacy. Professor Cipriani describes the importance of carrying out systematic reviews in assessing the effects of drugs in comparison to other drugs. For instance, he indicates that Verapamil, a calcium channel blocker used to treat hypertension, is not connected to any other calcium channel antagonists when a network of comparisons is drawn up.

Verapamil however was not found to cause significant positive effects compared to placebo or Lithium. Moreover, upon reviewing 6 double blind random controlled trials, it seems that overall no clear conclusions can be drawn about the effect of LTCCs in mania and bipolar disorder. Perhaps efforts should be directed elsewhere when searching for novel therapeutics for bipolar disorder. However, there seems to be speculation in the effects of Isradipine for the treatment of bipolar depression, a speculation that requires further investigation.

To follow, Professor Jeremy Hall from Cardiff concentrates on the CACNA1C gene, a gene affiliated with psychiatric risk. CACNA1C encodes for the 1 subunit for the L-type Cav1.2 calcium channels. Single nucleotide polymorphisms (SNPs) of this gene is associated with bipolar disorder and schizophrenia. Altered fear learning, reversal learning and early life stress are factors related to psychiatric disorders. Professor Hall then goes to describe how each of these factors can be studied in a CACNA1C (+/-) rat model to provide an insight into behavioural and neural physiological changes that occur as a result of altered VGCC function.

To end this symposium, Professor Liz Tunbridge from Oxford discusses the important issue of making brain selective calcium channel antagonists. As aforementioned calcium channels are also distributed within the heart. Therefore, means should be made to reduce possible adverse effects to the heart when targeting calcium channels within the brain for psychiatric disorders. With prior genetic evidence associated with VGCCs and psychiatric disorders, Professor Tunbridge is interested in the different splicing variations of the CACNA1C gene. Disparity in splicing could be the key mechanism that links non-coding polymorphisms to a disease process. A major component that needs to be considered when carrying out translational work in this field however is that splicing variations are poorly conserved in evolution, thus samples of human brain tissue would ideally need to be explored rather than samples from animal brains. It seems that there are some CACNA1C isoforms that are more enriched in the brain than in the heart in PCR studies. Professor Tunbridge hopes to fully characterise heart and brain VGCCs and exemplify their roles in bipolar disorder.

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