Feinberg
Northwestern Medicine | Northwestern University | Faculty Profiles

News Center

  • Categories
    • Campus News
    • Disease Discoveries
    • Clinical Breakthroughs
    • Education News
    • Scientific Advances
  • Press Releases
  • Media Coverage
  • Podcasts
  • Editor’s Picks
    • COVID-19
    • Cardiology
    • Cancer
    • Neurology and Neuroscience
    • Aging and Longevity
    • Artificial Intelligence in Medicine
  • News Archives
  • About Us
    • Media Contact
    • Share Your News
    • News Feeds
    • Social Media
    • Contact Us
Menu
  • Categories
    • Campus News
    • Disease Discoveries
    • Clinical Breakthroughs
    • Education News
    • Scientific Advances
  • Press Releases
  • Media Coverage
  • Podcasts
  • Editor’s Picks
    • COVID-19
    • Cardiology
    • Cancer
    • Neurology and Neuroscience
    • Aging and Longevity
    • Artificial Intelligence in Medicine
  • News Archives
  • About Us
    • Media Contact
    • Share Your News
    • News Feeds
    • Social Media
    • Contact Us
Home » Understanding How Calcium Channels Open and Close
Scientific Advances

Understanding How Calcium Channels Open and Close

By Sarah PlumridgeFeb 21, 2017
Share
Facebook Twitter Email
Murali Prakriya, PhD, associate professor of Pharmacology, and his team reveal how a calcium channel opens and closes and how mutations in this channel cause disease.
Murali Prakriya, PhD, associate professor of Pharmacology, and his team revealed how a calcium channel opens and closes and how mutations in this channel cause disease.

Northwestern Medicine scientists have identified the process that allows calcium channels to open and permit entry of calcium ions into cells, shedding light on how the channel operates and how mutations in the channel protein cause disease.

In the study, published in Nature Communications, the scientists identified the mechanism that keeps this particular calcium ion channel — called the Ca2+ release-activated Ca2+ (CRAC) channel — closed, as well as the movements in the channel pore that govern opening of the channel “gate.”

CRAC calcium channels are thought to exist in most, if not all, human cells, and play important roles in the activation of the immune system, muscle development and function and neuronal communication. When the channel pore opens, it allows calcium ions to flow into the cell, increasing the concentration of calcium in the cell and signaling functions such as gene transcription, proliferation and cell migration. A growing number of diseases are associated with abnormal CRAC channel function including immunodeficiency, muscular dystrophy and neurological diseases such as Alzheimer’s disease.

“Although the importance of CRAC channels for human health is now well recognized, how they operate at a molecular level remains poorly understood,” said senior author Murali Prakriya, PhD, associate professor of Pharmacology.

Megumi Yamashita, PhD, DDS, research assistant professor of Pharmacology, conducted electrophysiology and microscopy experiments to learn how the calcium channel’s gate uses a hydrophobic gating mechanism.
Megumi Yamashita, PhD, DDS, research assistant professor of Pharmacology, conducted electrophysiology and microscopy experiments to learn how the calcium channel’s gate uses a hydrophobic gating mechanism.

Megumi Yamashita, PhD, DDS, research assistant professor of Pharmacology, was the lead author of the study and Priscilla Yeung, graduate student in the Medical Scientist Training Program, also contributed to the paper.

“Megumi and Priscilla’s work reshapes our understanding of how the pores of these channels open in response to the stimulus, and specifically, it illuminates the molecular motions that govern the opening of the pore,” Prakriya said.

Using electrophysiology and microscopy techniques, the scientists observed that the CRAC channel’s gate uses a hydrophobic energy barrier that prevents charged calcium ions from passing through the pore in resting channels.

“In ion channels, the pore is usually water-friendly, so one way to close the pore is to have a oily, or hydrophobic, region that prevents the water-bound ions from going through — similar to the way that oil and water don’t mix. To open the pore, the hydrophobic region moves out of the way,” Prakriya said.

In addition to identifying the molecular structure that acts as the channel “gate,” the investigators also discovered that the pore-flanking domain of the channel rotates during channel opening. This allows the hydrophobic “gate” to move aside, thereby allowing the pore to become permeable to water and ions.

Using a supercomputer, collaborators at the University of Toronto ran molecular dynamic simulations, to show that this displacement of the hydrophobic gate eases an energy barrier, which increases water and ion occupancy in the pore when the channel opens.

The team also studied a human mutation in the calcium channel, which causes it to stay open, causing uncontrolled bleeding, muscle weakness and cognitive defects.

This illustration visualizes the CRAC channel signaling pathway, which plays important roles in the activation of the immune system, muscle development and function and neuronal communication.
This illustration visualizes the CRAC channel signaling pathway, which plays important roles in the activation of the immune system, muscle development and function and neuronal communication.

The investigators used the knowledge gained from the experimental and simulation studies to demonstrate that the human mutation disrupts the molecular stability of the hydrophobic gate, causing the pore to fill with water and letting ions travel through the channel.

“By understanding how the channel opens and closes, we can explain why human mutations cause abnormal channel activation,” Prakriya said. “In the long run, our hope is to use small molecule drugs that interact with the hydrophobic gate of the channel to manipulate its activity. This could correct defects in cell signaling and aid the quest for developing new therapies for immune, muscular and neurological diseases in which CRAC channels are involved.”

Next, Prakriya and his team plan to study the molecular rearrangements and signals that lead to the opening of the channel’s gate.

The research was funded by National Institutes of Health grants NS057499, GM114210, 5T32GM008382 and Canadian Institutes of Health Research grant MOP-130461.

Pharmacology Research
Share. Facebook Twitter Email

Related Posts

AI May Spare Breast Cancer Patients Unnecessary Treatments

Dec 7, 2023

Drug Extends Survival in Prostate Cancer with Genetic Mutations  

Dec 6, 2023

Pioneering Biochemist Craig Crews Named Winner of 2024 Kimberly Prize

Dec 5, 2023

Comments are closed.

Latest News

AI May Spare Breast Cancer Patients Unnecessary Treatments

Dec 7, 2023

Drug Extends Survival in Prostate Cancer with Genetic Mutations  

Dec 6, 2023

Pioneering Biochemist Craig Crews Named Winner of 2024 Kimberly Prize

Dec 5, 2023

Family Language Tied to Hospitalization Rates in Feverish Babies

Dec 5, 2023

New Therapeutic Strategies for Spinal Muscular Atrophy

Dec 4, 2023
  • News Center Home
  • Categories
  • Press Release
  • Media Coverage
  • Editor’s Picks
  • News Archives
  • About Us
Flickr Photos
2023-Sim-Open-House_161
2023-Sim-Open-House_127
2023-Sim-Open-House_108
2023-Sim-Open-House_106
2023-Sim-Open-House_118
2023-Sim-Open-House_068
2023-Sim-Open-House_069
2023-Sim-Open-House_027
2023-Sim-Open-House_155
2023-Sim-Open-House_161
2023-Sim-Open-House_127
2023-Sim-Open-House_108

Northwestern University logo

Northwestern University Feinberg School of Medicine

RSS Facebook Twitter LinkedIn Flickr YouTube Instagram
Copyright © 2023 Northwestern University
  • Contact Northwestern University
  • Disclaimer
  • Campus Emergency Information
  • Policy Statements

Type above and press Enter to search. Press Esc to cancel.