Molecular Understanding of Calcium-Sensitive Protein Could Explain the Mysteries of Long-term Memory – and More

AMHERST, Mass. – Margaret Stratton ponders a conundrum as she and her students study neuronal proteins in her lab: How can memory outlive the molecules that encode it?

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“The cells in the brain stay around for a long time, so we can understand at the cellular level how memories could last for decades,” says Stratton, associate professor of biochemistry and molecular biology. “But the components within those cells are recycled all the time – proteins specifically are degraded and remade on the order of seconds to hours, maybe weeks, but certainly not years.”

To advance her research into this big question, Stratton has been awarded a five-year, $1.8 million grant from the National Institute of General Medical Sciences, under the maximizing investigators’ research award (MIRA) program. MIRA grants are designed to enhance scientific productivity among talented and promising scientists, increasing the odds of important breakthroughs.

Stratton studies Ca2+/calmodulin dependent protein kinase II (CaMKII), a calcium-sensitive protein encoded by four genes in mammals.

“From mouse experiments, and also from mutations that are found in humans, we know that this protein is really crucial in learning and memory,” Stratton explains.

The ultimate goal is to figure out how long-term memory works at a molecular level by studying how CaMKII in neurons may act as a hub to maintain molecular signals over a long period of time.

“Once we have a handle on that, it will hopefully provide us with ways to intervene therapeutically when things go wrong, either because of a mutation in this specific protein or because of mutations in other proteins that impact long-term memory,” Stratton says.

The research has applications beyond understanding the molecular foundation of memory since CaMKII also is found in other calcium-coupled cells in the body, including cardiomyocytes in the heart and oocytes in the ovaries.

Stratton and her team will use sequencing, biochemistry, structural biology and cellular assays to study the roles of CaMKII in different cells and how this one enzyme accommodates such multifunctionality.

“The cool thing is that the versions of the protein that are found in those different cells are actually quite similar,” she says. “So what we learn in one system also informs us on the other systems.”

Once a better understanding of the molecular mechanisms exists, researchers can aim toward developing treatment approaches for a range of disorders.

The research holds promise of “far-reaching implications on therapeutic intervention for neurologic disease, cardiac dysfunction and infertility,” the grant summary concludes.