The aim of this project is to examine the elementary properties of a unique kind of calcium channel that responds to transient depolarizations with long-lasting increases in activity. Interestingly, we have observed this type of calcium channel activity in hippocampal neurons, but not in neurons of the sympathetic ganglia, suggesting that this voltage- dependent, long-term activation, or potentiation, may contribute to some aspect of the complex synaptic plasticity that has been observed in the hippocampus. At present, too little is known about this channel to speculate on its specific functions, although the possibilities are quite diverse, ranging from enhanced neuronal excitability to regulation of gene expression. For example, calcium channels of this type have been implicated in aging- related learning deficits. It is, therefore, critical to determine the precise biophysical characteristics of this potentiated activity under standard and physiologically-relevant conditions to make comparisons with other known calcium channel types and to gain insights into the effects this activity would have on neurons in situ. Furthermore, by determining how channel responsiveness is altered through the action of second messenger systems and by learning whether specific neurotransmitters can activate these same pathways in hippocampal neurons, important insights into the dynamic regulation of this calcium channel potentiation can be obtained. Moreover, by using a combination of kinetic modeling and related experimental protocols, it will be possible to gain a fundamental understanding of the mechanisms that underlie long-lasting calcium channel activity. To accomplish these goals, single-channel and whole-cell patch clamp recordings will be made from hippocampal neurons. A variety of stimulation protocols and recording conditions will be used to determine the time course and voltage-dependence of the potentiated activity. In addition, a collaborative effort to identify the molecular composition of this calcium channel will be initiated during the time covered by this grant application. By systematically studying a calcium channel with such intriguing properties, we will establish the strong foundation necessary to understand the functional role and clinical relevance of calcium channel potentiation in the hippocampus.
