Grant: Operating Grant

The entry of calcium ions into cells is mediated by a class of protein that responds to electrical signals by opening a calcium selective pore (called calcium channels). Calcium channels are involved in a large number of normal physiological processes including muscle contraction, hormone secretion and all electrical signaling in the nervous system. The alteration of calcium entry into cells is highly detrimental and some human diseases can be treated by drugs that inhibit calcium channels including, migraines, chronic pain, epilepsy, hypertension and heart failure. Utilizing gene cloning techniques we have isolated a family of ten genes encoding calcium channels. To characterize the channels outside of the body we introduce the cloned genes into cultured cell lines. By determining the electrical and pharmacological properties of the cloned calcium channels the work has accounted for many of the properties of calcium channels found in nerve, smooth muscle and heart. We have found that in addition to the ten calcium channel genes, many more functional channel subtypes can be generated by a process known as "splicing". The recent work shows that in genetic animal models of human disease only certain calcium channel splice variants contribute to the disease pathophysiology. The results suggest that genetic mutations preferentially affect only a fraction of the possible channel subtypes and the proposal aims to investigate the underlying basis for where each of the variants is expressed in cells and tissues, when during development each is expressed, and how particular genetic mutations selectively affect channel properties to cause physiological aspects relevant to disease. By identifying the specific calcium channel slice variants involved in disease the work will provide the pharmaceutical industry with new and valuable tools for the design and testing of new drugs predicted to be more specific and to have less side-effects than current treatments.