Calcium is widely known for its role in maintaining strong bones and teeth, but it is also one of the body’s most important cellular messengers. Calcium signals help regulate muscle contraction, nerve function, immune cell activation, and many other physiological processes. Cells rely on calcium signals to determine when and how strongly to respond, so calcium movement must be tightly controlled.
At the cellular level, one of the major calcium signaling pathways is known as store-operated calcium entry (SOCE). In this pathway, the endoplasmic reticulum, the major calcium store within the cell, acts as a sensor and delivery system. When calcium levels in the endoplasmic reticulum decrease, protein stromal interaction molecule 1 (STIM1) detects the change and activates ORAI channels in the cell membrane. ORAI1 forms the pore of calcium release-activated calcium channels (CRAC channels), allowing extracellular calcium to enter the cytosol and trigger downstream signaling.
Understanding how this pathway works and how it can be controlled when it doesn’t is the focus of research led by Yubin Zhou, director of the Center for Translational Cancer Research at Texas A&M Health Biosciences Institute and professor at the Texas A&M Naresh K. Vashisht School of Medicine. Working with collaborators Guolin Ma, Ph.D., of MD Anderson and Dr. Qing Deng, Purdue University, Zhou’s team recently published a study. nature communications They describe engineered CRAC channel blocking binders (CRABs) that can selectively interfere with STIM-ORAI communication and reduce calcium entry through CRAC channels.
Tien-Hung Lan, a Texas A&M Health research project scientist in Zhou’s lab and co-author of the study, emphasized the importance of calcium signaling for basic cellular functions.
Calcium signals are essential for cell function. There are several routes by which calcium can enter cells, and CRAC channels are one of the main routes. They are particularly important in immune cells, including T cells. ”
Tien-Hung Lan, Texas A&M Health
T cells rely on CRAC channels to maintain calcium signals that activate transcription factors such as NFAT that help activate immune cells and promote cytokine production. Defects in this pathway can prevent immune cells from responding properly. When activated excessively or chronically, it can cause disease.
Previous studies have shown that CRAC channel activity is highly dependent on two core components. ORAI1 forms calcium-selective channels in the cell membrane. STIM1, located in the endoplasmic reticulum membrane, senses when internal calcium stores are depleted. Once activated, STIM1 moves to the ER cell membrane contact site and binds to ORAI1, opening the channel and allowing calcium influx.
“There has been an ongoing effort in the community to understand how STIM and ORAI proteins interact,” Lan said. “While studying this interface, we realized that ORAI-derived peptides could be used as decoys to compete for STIM1 binding and prevent endogenous channel opening.”
Competitive inhibition is a process by which one molecule can bind to a protein at the intended position of another molecule. Unlike traditional channel blockers, the research team designed a peptide binder that prevents STIM1 from engaging the ORAI channel, thereby reducing calcium influx and downstream signaling. To test whether these peptide binders could counteract pathological CRAC channel activation, Zhou’s lab used a zebrafish model of Stormoken syndrome. Stormoken syndrome is a rare multisystem disease associated with excessive CRAC channel activity. Patients may experience low platelet counts (thrombocytopenia), bleeding problems, muscle weakness or convulsions, miosis (pinpoint pupils), and other symptoms.
“Gain-of-function mutations will have an impact,” Zhou said. “The cells die because too much calcium enters them. Secondly, it can cause muscle weakness and spasms, and many patients also have bleeding problems.”
In their study, the researchers showed that the company’s engineered binder, named CRAB for CRAC channel blocking binder, specifically targets CRAC channels and helps restore production of essential cells called platelet progenitors, which are needed to prevent abnormal bleeding.
Zhou’s lab, which designed the binder, is now looking at how the platform can be adapted for broader applications, including future strategies to improve cellular immunotherapies. CAR-T cell therapy has revolutionized the treatment of some blood cancers, but safety and durability remain challenges. Excessive or chronic calcium signaling can contribute to persistent signaling, T cell depletion, and cytokine production.
“CAR-T cell therapy has significant side effects and durability challenges, and calcium signaling is one pathway that can lead to overactivation and fatigue,” Lan said. “If we can modulate this pathway, rather than permanently block it, we may be able to expand the range of treatments and improve the performance of genetically engineered immune cells.”
What does this mean for patients diagnosed with CRAC channel-related diseases or cancers treated with cellular immunotherapy? It may mean another step toward precision medicine. This provides a proof of concept for a more precise approach, i.e., genetically encoded tunable control of major calcium influx pathways using light or chemicals.
Still, Chou said the study results point to broader goals in precision medicine.
“The long-term vision is to create molecular tools that can precisely tune cell signaling,” Zhou said. “CRAB provides us with a way to put a tunable brake on T cell activity. This could help us study disease mechanisms and ultimately design safer and more controllable immune cell-based therapies.”
sauce:
Reference magazines:
Liu, X. Others. (2026). Engineering genetically encoded programmable calcium channel blocking binders. Nature Communications. DOI: 10.1038/s41467-026-71769-2. https://www.nature.com/articles/s41467-026-71769-2
