A role for HERG in the Hippocampus?

Ion channels represent the central elements of rapid signaling in electrically excitable cells. For instance, the continuous, rhythmic heartbeat is generated by cardiac action potentials which result from the coordinated activation and inactivation of Na+ -, Ca2+-, and K+ channels. K+ channels are critically involved in setting the resting membrane potential and in the termination of action potentials. The HERG gene product represents a specific example for the importance of this functional modulation: HERG channels underlay the cardiac inward rectifier K+ current IKr that initiates the depolarization of cardiac action potentials and suppresses the generation of premature afterbeats. Impaired function of HERG in patients that are affected by a hereditary disease termed long- QT syndrome 2 (LQT2), causes a high risk of ventricular fibrillation and sudden death in the case of certain arrhythmias. Even though playing a prominent role in cardiac function, HERG transcripts are also detected in brain and HERG has initially been cloned from human hippocampus. However, the functional significance of HERG channels in brain has not yet been investigated and therefore remains speculative. Due to its biophysical properties, HERG is likely be involved in the modulation of neuronal action potentials. The goal of the proposed project is the identification and functional characterization of a HERG current phenotype in isolated hippocampal neurons by using K+ channel pharmacology and the patch-clamp technique. Hippocampal pyramidal cells are important for memory and learning. Multiple types of K+ channels have been identified in brain by electrophysiological recordings, but the characterization of currents flowing over the rapid time scale of the neuronal action potential has not been attempted before. By using large patch pipettes and isolated hippocampla neurons this limitation in the functional examination of HERG and other K + channels can be overcome. Moreover, this experimental approach might potentially aid the development of novel drugs that function as cognition enhances and are effective in the treatment of neurological disorders such as Alzheimer`s disease.