Research
K+ Efflux

Investigator: Lech Kiedrowski, Ph.D.

My laboratory probes the mechanisms operative in glutamate-induced neuronal death, including the relevance of glutamate receptor activation to psychiatric disorders.

The N-methyl-D-aspartate (NMDA) class of glutamate receptors is widely distributed within the brain and the spinal cord, and has been linked to a variety of complex physiological mechanisms, such as regulation of the development of the nervous system, memory formation, or generation of rhythmic motor activity. Activation of these receptors has also been linked to acute damage of the nervous system following stroke or ischemia, as well as to several neurodegenerative diseases such as amyotropic lateral sclerosis.

Ca²⁺, Na⁺, and K⁺ permeate NMDA receptor channels, and it is well established that an excessive NMDA-induced Ca²⁺ influx is responsible for the NMDA-induced neuronal death. It is still unclear, however, whether the NMDA-induced Na⁺ and K⁺ fluxes also play a role in excitotoxicity. The NMDA-induced Na⁺ influx depolarizes the plasma membrane and affects Ca²⁺ homeostasis in a complex manner: 1) by activating voltage-sensitive Ca²⁺ channels; 2) by activating Ca²⁺ influx via the plasma membrane Na⁺/Ca²⁺ exchanger (NaCaX); and 3) by reducing the electrochemical driving force for Ca²⁺ influx across the plasma membrane. Our recent data indicate that Ca²⁺ influx via the NaCaX may play a much more important role in excitotoxicity than previously expected.