APPS November 2002 Meeting Abstract 241

During prolonged depolarisation of excitable cells, some voltage-activated, tetrodotoxin (TTX)-sensitive Na⁺ channels are resistant to inactivation and can continue to open for long periods of time, resulting in a persistent sodium current (I_NaP). The amplitude of I_NaP is normally small, activates at potentials close to the resting membrane potential and is more susceptible to Na⁺ channel blocking drugs such as TTX. This behaviour of Na⁺ channels may endow excitable cells with an intrinsic propensity for rhythmic, spontaneous firing but may at other times be quite deleterious and cause cell death. Mutations in Na⁺ channel genes that cause increases in I_NaP have been identified in disorders that cause episodic dysfunction of heart, skeletal muscle, and brain. Both stroke and cardiac arrhythmias are often caused by the occlusion of an artery that deprives the brain or heart of O₂. Hypoxia increases the amplitude of I_NaP in ventricular and hippocampal cells^1,2 and drugs that block Na⁺ channels can prevent increases in intracellular Na⁺ and Ca²⁺ and damage to cardiac muscle and neurones during hypoxia^3,4. It is proposed that an increased inflow of Na⁺ during hypoxia increases the intracellular Na⁺ concentration, which in turn reverses the Na⁺/Ca²⁺ exchanger so that intracellular Ca²⁺ increases. An increase in I_NaP and intracellular Ca²⁺ can therefore cause hyperexcitability, cardiac arrhythmias and cell damage. The question remains how do persistent Na⁺ channels sense reductions in PO₂? The answer to this question may provide an important anti-ischaemic drug target. Many different types of ion channels are regulated by O₂ tension⁵ and this “O₂-sensing” is thought to involve redox-modulation of a closely associated membrane-bound protein. We are currently exploring the nature of this auxiliary protein and the Na⁺ channel subunits that are involved in O₂-sensing by using native cells, pharmacological tools as well as recombinant Na⁺ channels.