The VICC.ORG Directory of Doctors, Healthcare Providers & Researchers

Roger J. Colbran, Ph.D.

Professor of Molecular Physiology and Biophysics
VICC Member
Researcher

Contact Information:

Vanderbilt University Medical Center
724 RRB
Nashville, TN 37232-0617
615-936-1630

Research Specialty

Structure, function and subcellular targeting of Ca2+/calmodulin-dependent protein kinase II in health and disease

Research Description

Many hormones and neurotransmitters act on cell surface receptors to elevate cytosolic levels of soluble second messengers such as cyclic AMP and calcium. These molecules diffuse freely but the dynamics of second messenger generation and removal are such that their concentrations are only elevated locally and transiently. This spatial heterogeneity implies that cellular proteins that are sensitive to second messengers have discrete subcellular localization(s). The overall goal of this laboratory is to understand how localization of signal transduction molecules is achieved and how this impacts cellular regulation.

Multiple synaptic roles for calcium/calmodulin-dependent protein kinase II (CaMKII)

Neurons are highly asymmetric cells due to their extensive dendritic and axonal processes. Moreover, the dendrites are covered with thousands of dendritic spines that receive synaptic inputs from many different neurons. Each synapse can be independently modulated on time scales ranging from milliseconds to the lifetime of the animal. Of particular interest are long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus, opposing forms of synaptic plasticity that are induced by calcium influx via NMDA-type glutamate receptors. High frequency stimulation of a synapse generally results in induction of LTP, where as low frequency stimulation induces LTD. Thus, calcium-dependent signaling molecules are able to generate different physiological responses depending on the frequency with which a synapse is stimulated. Furthermore, LTP and LTD are confined to synapse(s) that received the initial high or low frequency stimulation, respectively, without any “spill-over” to nearby unstimulated synapses. The major focus of this laboratory is to determine the molecular mechanisms that permit synapse specific generation of LTP or LTD. Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a pivotal role in synaptic plasticity, learning and memory.

CaMKII as an integrator of diverse calcium signals

Dodecameric CaMKII holoenzymes require calcium and calmodulin for initial activation. Autophosphorylation at Thr286 converts the kinase to a form that has calcium/calmodulin-independent kinase activity, requiring a protein phosphatase to be inactivated. The activity of PP1γ1 targeted to the neuronal postsynaptic density by spinophilin and/or neurabin is believed to play a critical role in gating CaMKII autophosphorylation during synaptic plasticity. Thus, the opposing actions of calcium/calmodulin and protein phosphatases allow CaMKII to integrate information conveyed by the frequency, amplitude and duration of transient elevations of calcium that occur at synapses and induce LTP or LTD. In addition, it is very well established that Thr286 autophosphorylation is essential to normal synaptic plasticity, learning and memory.

Mechanisms of CaMKII Targeting

Our central hypothesis is that specific synaptic actions of CaMKII require the assembly of specific multiprotein complexes containing CaMKII and downstream mediators of individual signaling pathways, and are opposed by specific PP1 complexes. We are investigating several synaptic proteins that dynamically interact with CaMKII or PP1 by distinct biochemical mechanisms, including subunits of NMDA-type glutamate receptors and voltage-gated calcium channels, densin-180, alpha-actinin, spinophilin and neurabin, as well as some novel interactions. Our goal is to understand the biochemical/structural basis for these interactions and use this information to help us identify specific roles for these interactions in controlling synaptic function both physiologically (e.g., LTP/LTD) and pathologically (e.g., in Parkinson's Disease). These studies employ a diverse array of biochemical, molecular and cell biological, immunological, proteomic, fluorescent imaging and electrophysiological techniques.

Publications


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