Ranging from fertilization and cell death to contraction and secretion, transient increases in intracellular calcium (Ca2+) levels regulate fundamental biological processes throughout the body. In the nervous system, neuronal communication requires Ca2+ signaling, as does the regulation of the strength and specificity of neuronal connections. Ca2+ alters cell function by altering the biological activity of proteins. This process may involve a direct affect through Ca2+ altering a protein’s conformation as well indirect affects through the activation of kinases and phosphorylation. Understanding the mechanisms by which protein kinases and Ca2+ binding proteins translate Ca2+ signals into specific changes in cell function is the focus of my laboratory.
My current research efforts are concentrated on two Ser/Thr protein kinases: 1) a Ca2+/calmodulin activated protein kinase (CaMKII) essential to synaptic plasticity and 2) mitogen-activated protein kinases (MAP kinases), which are activated by cell stress and growth factors to regulate pain, synaptic plasticity, and addiction. Although CaMKII is found throughout the body, it’s best known as a “cognitive kinase” due to its role in learning and memory and “machine-like” behavior in decoding Ca2+ signals. MAP kinases are downstream effectors of multiple kinases, including CaMKII. MAP kinase activity may produce long-term changes in cell function by changes in gene transcription. Thus, the universal role of CaMKII in Ca2+ signal transduction as well the potential for MAP kinases to remodel long-term changes in cell function, make these kinases, as well as their regulators and substrates, important therapeutic targets for a number of important diseases throughout the body, ranging from heart disease and diabetes to addiction and cerebral ischemia.
The primary goal of my laboratory is to elucidate how protein kinases function as specialized molecular machines and assemble with their substrates and regulators to form signaling modules. In doing so, we combine traditional biochemical and biophysical techniques in conjunction with fluorescent imaging approaches to characterize kinases and their substrates in vitro and in living cells. The long-term goals of our research efforts are to identify novel protein interactions and regulatory mechanisms that underlie synaptic function and plasticity in the nervous system.