Role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in normal synaptic signaling and in neuropsychiatric disorders
Many hormones and neurotransmitters act on cell surface receptors to elevate cytosolic levels of soluble second messengers, such as calcium. However, many physiological responses are driven by highly localized increases in calcium concentrations. This is particularly true in highly asymmetric cells such as neurons. The extensive dendritic processes of a mature neuron are decorated with thousands of dendritic spines that receive distinct glutamatergic synaptic inputs. Changes in calcium concentrations within an individual dendritic spine can drive dynamic changes in the structure and strength of that specific synapse on time scales ranging from milliseconds to the lifetime of the animal. These alterations are essential for normal learning and memory. Moreover, abnormal synaptic structure and function are associated with a wide range of neuropsychiatric disorders. The major focus of this laboratory is to determine the molecular mechanisms that regulate these processes, with a main focus on the role of calcium/calmodulin-dependent protein kinase II (CaMKII).
CaMKII subunits associate to form dodecameric holoenzymes that are activated by calcium and calmodulin to drive autophosphorylation at Thr286. It is very well established that Thr286 autophosphorylation is essential for normal synaptic plasticity, learning and memory. Mice with CaMKII mutations exhibit deficits in synaptic regulation. In fact, CaMKII can regulate many downstream targets, and CaMKII has been shown to be critical in making synapses bigger/stronger or smaller/weaker under different physiological conditions. However, specific molecular deficits that contribute to the wide range of behavioral abnormalities displayed by different CaMKII mutant mice are largely unknown.
The overarching hypothesis driving research in the Colbran lab is that specific synaptic functions of CaMKII are determined by interactions with a diverse array of CaMKII-associated proteins (CaMKAPs). Thus, the specific physiological role of activating CaMKII in an individual synapse is determined by the repertoire of co-localized CaMKAPs. We are investigating several synaptic CaMKAPs, including subunits of NMDA-type glutamate receptors and voltage-gated calcium channels, densin-180, Shanks, alpha-actinin, spinophilin, neurabin, GPCRs and 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 and in a variety of pathological states. These studies employ a diverse array of biochemical, molecular and cell biological, immunological, proteomic, fluorescent imaging, electrophysiological, genomic and behavioral techniques.