Calcium Channels Play Essential Role in Astrocyte Activity

Anna Toth, a doctoral and medical student in the Medical Scientist Training Program, was the first author of the study that identified the critical role CRAC channels play in the activity of brain cells called astrocytes.

Northwestern Medicine scientists have identified the critical role that a specific ion channel plays in the activity of brain cells called astrocytes.

In the study, published in Science Signaling, the scientists established the Ca2+ release-activated Ca2+ (CRAC) channel— as a major route for the influx of calcium ions into the star-shaped glial cells in the hippocampus.

Furthermore, the investigators demonstrated that stimulation of CRAC channels in astrocytes triggers the release of gliotransmitters such as adenosine triphosphate (ATP), which is an important mode of intercellular communication between astrocytes and neighboring neurons.

The study was led by Murali Prakriya, PhD, professor of Pharmacology. Anna Toth, a student in the Medical Scientist Training Program (MSTP) was the first author.

“Our results show that CRAC channels are essential for the ability of astrocytes to respond to cues from their environment and influence the activity of neighboring neurons,” said Prakriya, also a member of the Robert H. Lurie Comprehensive Cancer Center.

The study that identified the critical role that a specific ion channel plays in the activity of brain cells called astrocytes was led by Murali Prakriya, PhD, associate professor of Pharmacology.

“In other words, CRAC channels may be important for astrocytes’ ability to ‘listen’ and ‘talk’ to their neuronal partners to affect neural function,” Toth said.

Astrocytes are the primary glial, or non-neuron, cells in the central nervous system, performing myriad functions essential for normal neural activity in the brain, including homeostasis, nervous tissue growth, metabolic support, and regulation of blood flow.

CRAC channels are present in the plasma membrane of brain astrocytes and are formed by the Ca2+ ion channel protein, Orai1, and activated by the endoplasmic reticulum Ca2+ sensor protein, STIM1.

Using mouse models, the team examined the crucial role of Orai1 and STIM1 in mediating calcium ion signaling and modulating the release of gliotransmitters.

Astrocytes deficient in CRAC channels were compromised in their ability to release gliotransmitters and impaired in their ability to modulate the excitability of neurons in brain circuits. Abnormal CRAC channel function has been previously associated with disorders including immunodeficiency and myopathy, and neurological diseases such as Alzheimer’s disease, cognitive disability, and epilepsy.

“The findings deepen our understanding of astrocyte physiology and are relevant for future studies looking at neurological disorders involving dysregulated Ca2+ signaling in astrocytes,” said Prakriya. “Our study identifies a potential novel therapeutic target for modulating neuronal excitability in brain injuries and neurological diseases.”

Additional Northwestern study authors include Kotaro Hori, MD, PhD; Michaela Novakovic, Natalie Bernstein, and Laurie Lambot, PhD.

The study was supported by National Institutes of Health grants NS057499 and R01 GM114210. Anna Toth was supported by NIH predoctoral fellowship F30 NS090817, the Julius B. Kahn fellowship, and the Medical Scientist Training Program.