Grant: Operating Grant

The rapid entry of calcium ions into nerve 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 controlling neurotransmitter release and electrical activity throughout the nervous system. The alteration of normal calcium entry into cells is highly detrimental and some human diseases can be treated by drugs that block calcium channels including, migraines, chronic pain, epilepsy, hypertension and heart failure. Utilizing gene cloning techniques we have previously isolated a family of ten genes encoding calcium channels and characterized their electrical and pharmacological properties. We have discovered that in addition to the ten calcium channel genes, many more functional channel subtypes are generated by a process known as "splicing". Interestingly, examining genetic animal models of human disease we find that 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 our current proposal aims to investigate the underlying basis as to how each variant distinctly cause pathophysiological aspects relevant to disease. Through identifying the roles of specific calcium channel variants involved in disease the work will provide new targets and valuable tools for the design and testing of new drugs with better efficacy and fewer side effects than existing treatments.