Molecular mechanisms underlying inactivation of voltage-

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Very little is known about how neurons encode information in the presence of noise - a ubiquitous feature of the nervous system at both the membrane level and at the level of random synaptic inputs to any individual neuron from other nerve cells. We have investigated this question using squid giant axons made bistable with a moderately alkaline intracellular mileau. Bistability may be characteristic feature of neurons in the brain. Low level noise injected into the squid axon preparation produced a switch from its firing mode to its quiescent mode without a switch back to the firing mode. This observation may be useful in designing devices to control hyperexcitability during epileptic seizures. Higher levels of noise produced burst of firing, which may be a mechanisms used by the brain for short term memory formation. A subsidiary feature of this project concerns the mechanisms by which changes in intracellular pH (pHi) modify ion channels underlying nerve excitability. This lab previously found that a shift of pHi in squid axons produced a shift of slow inactivation of the potassium ion current, IK, along the voltage axis. The lab recently found a lack of such an effect in Shaker K channels heterologously expressed in Xenopus oocytes. The molecular mechanisms underlying slow inactivation in the latter channel appear to differ from those of the squid channel. An investigation of the primary amino acid sequences of both K channel types suggest five possible targets for the pHi effect in the squid channel. We are currently engineering those residues out of the squid channel to see if there is a concomitant removal of the voltage shift of slow inactivation. A further series of experiments will involve an attempt to engineer those residues into the Shaker channel to see if the voltage shift can be added to its slow inactivation process. These experiments may further elucidate the mechanisms underlying this gating feature which is common to all types of voltage-gated channels.