Researchers gain insight into how ion channels control heart and brain electrical activity

August 16, 2013 by Sathya Achia Abraham
Proposed model of Gß?-GIRK channel interaction. Gß? (transparent yellow, ribbon representation) is seen interacting with two adjacent GIRK channel subunits (red and blue, surface representation). A key amino acid identified in the study, Leucine 55 of Gß (yellow spheres), can be seen interacting with the cleft formed by adjacent GIRK subunits. Credit: Rahul Mahajan/VCU

Virginia Commonwealth University researchers studying a special class of potassium channels known as GIRKs, which serve important functions in heart and brain tissue, have revealed how they become activated to control cellular excitability.

The findings advance the understanding of the interaction between a family of signaling proteins called G proteins, and a special type of ion pore called G protein-sensitive, inwardly rectifying potassium (GIRK) channels. The findings may one day help researchers develop targeted drugs to treat conditions of the heart such as .

In the study, published this week in the Online First section of Science Signaling, a publication of the American Association for the Advancement of Science (AAAS), researchers used a to predict the interactions between G proteins and a GIRK channel.

Rahul Mahajan, a M.D./Ph.D. candidate in the VCU School of Medicine's Department of Physiology and Biophysics, undertook this problem for his dissertation work, under the mentorship of Diomedes E. Logothetis, Ph.D., chair of the Department of Physiology and Biophysics and the John D. Bower Endowed Chair in Physiology in the VCU School of Medicine. They developed a model and tested its predictions in cells, demonstrating how G proteins cause activation of GIRKs.

"Malfunctions of GIRK channels have been implicated in chronic atrial fibrillation, as well as in drug abuse and addiction," said Logothetis, who is an internationally recognized leader in the study of and cell signaling mechanisms.

"Understanding the structural mechanism of G?? activation of GIRK channels could lead to rational based drug design efforts to combat chronic atrial fibrillation."

In chronic atrial fibrillation, the GIRK channel is believed to be inappropriately open. According to Logothetis, if researchers are able to target only the specific site that keeps the channel inappropriately open, then any unrelated channels could be left unaltered, thus avoiding unwanted side effects.

Crystal structures of GIRK channels, which preceded the current study, have revealed two constrictions of the ion permeation pathway that researchers call "gates": one at the inner leaflet of the membrane bilayer and the other close by in the cytosol, which is the liquid found inside cells.

"The structure of the G?? -GIRK1 complex reveals that G?? inserts a part of it in a cleft formed by two cytosolic loops of two adjacent channel subunits," Logothetis said. "This is also the place where alcohols bind to activate the channel. One can think of this cleft as a clam that has its shells either open or shut closed. Stabilization of this cleft in the 'open' position stabilizes the cytosolic gate in the open state."

GIRKs are activated when they interact with G proteins coupled to receptors bound to stimulatory hormones or neurotransmitters. In heart tissue, acetylcholine released by the vagus nerve activates these channels, which hyperpolarize the membrane potential and slow heart rate. In , GIRKs inhibit excitation by acting at postsynaptic cells.

G proteins are composed of three subunits, a, b, and g. Since 1987, researchers have known that the Gbg subunits directly activate the atrial GIRK channel, but an atomic resolution picture of how the two proteins interact remained elusive until now.

Moving forward, the team would like to use computational and experimental approaches to build and test the structures of the rest of the components of the G protein complex – for example, the Ga subunits and the G protein-coupled receptor – around the G??- complex, which is the structure the team has already achieved.

The study is titled: "A Computational Model Predicts the Action of G??; at an Inter-Subunit Cleft to Activate GIRK1 Channels."

Explore further: Water molecules control inactivation and recovery of potassium channels (w/ Video)

More information: stke.sciencemag.org/cgi/conten … /sigtrans;6/288/ra69

Related Stories

Water molecules control inactivation and recovery of potassium channels (w/ Video)

July 28, 2013
Just 12 molecules of water cause the long post-activation recovery period required by potassium ion channels before they can function again. Using molecular simulations that modeled a potassium channel and its immediate cellular ...

Scientists discover how to design drugs that could target particular nerve cells

November 10, 2011
(Medical Xpress) -- The future of drug design lies in developing therapies that can target specific cellular processes without causing adverse reactions in other areas of the nervous system. Scientists at the Universities ...

Recommended for you

Manipulating a type of brain cell gets weight loss results in mice

July 28, 2017
A new study has found something remarkable: the activation of a particular type of immune cell in the brain can, on its own, lead to obesity in mice. This striking result provides the strongest demonstration yet that brain ...

Team finds link between backup immune defense, mutation seen in Crohn's disease

July 27, 2017
Genes that regulate a cellular recycling system called autophagy are commonly mutated in Crohn's disease patients, though the link between biological housekeeping and inflammatory bowel disease remained a mystery. Now, researchers ...

Study finds harmful protein on acid triggers a life-threatening disease

July 27, 2017
Using an array of modern biochemical and structural biology techniques, researchers from Boston University School of Medicine (BUSM) have begun to unravel the mystery of how acidity influences a small protein called serum ...

CRISPR sheds light on rare pediatric bone marrow failure syndrome

July 27, 2017
Using the gene editing technology CRISPR, scientists have shed light on a rare, sometimes fatal syndrome that causes children to gradually lose the ability to manufacture vital blood cells.

Post-stroke patients reach terra firma with new exosuit technology

July 26, 2017
Upright walking on two legs is a defining trait in humans, enabling them to move very efficiently throughout their environment. This can all change in the blink of an eye when a stroke occurs. In about 80% of patients post-stroke, ...

Molecular hitchhiker on human protein signals tumors to self-destruct

July 24, 2017
Powerful molecules can hitch rides on a plentiful human protein and signal tumors to self-destruct, a team of Vanderbilt University engineers found.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.