Grant: Operating Grant

Control over the excitability of neurons in the brain depends on the activity of calcium-gated potassium channels that inhibit membrane voltage to reduce synaptic responses and action potential (spike) firing. Despite the critical role for these channels, only two classes of potassium channels gated by calcium entry were believed to be expressed in brain neurons: big conductance (BK) and small conductance (SK) channels. The properties of BK and SK channels in controlling spike repolarization and afterhyperpolarizations (AHPs) have been thoroughly characterized in structures like the hippocampus, where loss of potassium channel inhibition can lead to epileptiform discharge. However, a slow AHP that generates the most significant hyperpolarizing response in hippocampal cells has gone without molecular identification for over 25 years. We have discovered that an intermediate conductance (IKCa) potassium channel is expressed in hippocampus and other brain regions, contrary to all previous beliefs. Moreover, IKCa channels account for the majority of the slow AHP to control the degree of temporal summation of chemically transmitted potentials as well as action potential output. As such we are in a unique position to characterize the properties and roles of a new class of potassium channel in the brain. This work will be important in providing a molecular basis for a key inhibitory element that has eluded identification, the first step in potentially identifying therapeutic agents important for treating dysfunctional neuronal output in disease states.