Paul Mermelstein

Calcium Signaling and Cellular Excitability.

Mammalian neurons face the daunting task of integrating signals from tens of thousands of synaptic contacts. Based upon the temporal and spatial cues by which neurotransmitters are released, as well as inputs from more systemic signals (e.g. hormones) cells decide whether to become quiescent, fire one or a series of action potentials and/or alter their responses to future stimuli. But for long term changes in synaptic plasticity to occur, new proteins must be generated.

My lab focuses on elucidating (1) the mechanisms by which neurons decipher synaptic cues that are meant to activate protein synthesis (2) the second messenger systems that relay signals from the synapse to the nucleus leading to activity-dependent gene expression and (3) the functional consequences of expressing these transcripts into protein. Using a wide variety of powerful cellular and molecular techniques, we have found that repeated stimulation of excitatory synapses causes calcium to enter a cell through multiple ligand-voltage-gated ion channels. However, only calcium entering through a specific class of calcium channel (L-type) triggers the signal transduction pathways that lead to the activation of several different transcription factors and the synthesis of new protein.

Currently, we are focusing our attention on two separate transcription factors, CREB and NF-AT, both of which have been implicated in memory consolidation. Signaling to CREB and NF-AT rely heavily upon the calcium-binding protein calmodulin. However, while CREB-dependent gene expression is regulated by a series of calmodulin-dependent protein kinases, NF-AT activation is through the calmodulin-dependent protein phosphatase calcineurin. Future research will examine how L-type calcium channels differentially regulate these transcription factors, the mechanism by which L-type channels are 'privileged' in their ability to signal changes in the nucleus, and the alterations in cellular excitability that occur following CREB- and NF-AT-dependent gene expression. To do so, the lab will employ electrophysiological, fluorescent imaging, gene manipulation and transfection as well as DNA microarray techniques.Research examining this form of neuroplasticity will undoubtedly help neuroscientists better understand a variety of experimental themes such as learning and memory, neuronal development and drug addiction.