Unravelling the Mysteries of Calcium Channel Regulation

Scientists have addressed a long-standing controversy behind the molecular players mediating calcium signaling, a biological process that coordinates a wide array of physiological responses, according to findings published in the Proceedings of the National Academy of Sciences.

Murali Prakriya, PhD, the Magerstadt Professor of Pharmacology, was co-corresponding author of the study.

Cellular calcium signaling plays a crucial role in the physiology of the human body, including regulating gene expression, programmed cell death and various immune responses.

Until now, the role of transient receptor potential canonical (TRPC) channels in mediating store-operated calcium entry (SOCE), a major calcium entry process, was unclear.

“This study addresses a historical controversy around a process called store-operated calcium entry, which exists in all cells and is especially important in the immune system,” said Murali Prakriya, PhD, the Magerstadt Professor of Pharmacology and co-corresponding author of the study. “For a long time, the molecular basis of this pathway was unknown. In 2006, we and others identified a new class of ion channels called Orai channels in mediating SOCE, but whether Orai works together in conjunction with TRPC channels in causing SOCE was unclear.”

In the study, Prakriya and his collaborators studied genetically engineered mice without all TRPC genes. Investigators found that the depletion of cellular calcium stores activated SOCE channels formed exclusively by Orai1 molecules in these mice.

Surprisingly, the absence of all seven TRPC genes did not significantly affect store-operated or receptor-operated calcium channels, Prakriya said.

“Using very sensitive electrophysiological approaches, we were able to show that when we deleted all the seven mouse TRPC channels, store-operated calcium entry and receptor-operated calcium entry is unaffected,” said Prakriya, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

The findings prove that calcium ion replenishment of intracellular stores in cells does not rely on TRPC proteins, settling a decades-long debate within the scientific community.

In addition to providing new insights into the intricate mechanisms of cellular calcium entry, the findings may be useful for developing therapeutic interventions targeting calcium-related disorders.

“One surprising finding was that mice lacking all seven TRPC genes even survive. This indicates that TRPC channels are not essential for viability. Yet, these mice do show phenotypes,” Prakriya said. “These mice appear to be very obese. That opens up the possibility that the TRPC channels play a very important role in cellular metabolism and in body metabolism.”

Megumi Yamashita, PhD, DDS, research associate professor of Pharmacology, was a co-first author of the study.

The study was supported by the Intramural Research Program of the National Institutes of Health (Z01 ES101684) and NIH Research Grants R01 NS057499, R01 AT011162, R01CA195727 and R35 NS132349.