Equations reveal the rebellious rhythms at the heart of nature

From the beating of our hearts to the proper functioning of our brains, many systems in nature depend on collections of ‘oscillators’; perfectly-coordinated, rhythmic systems working together in flux, like the cardiac muscle cells in the heart.

Unless they act together, not much happens. But when they do, powerful changes occur. Cooperation between neurons results in brain waves and cognition, synchronized contractions of cardiac cells cause the whole heart to contract and pump the blood around the body. Lasers would not function without all the atomic oscillators acting in unison. Soldiers even have to break step when they reach a bridge in case oscillations caused by their marching feet cause the bridge to collapse.

But sometimes those oscillations go wrong.

Writing in the journal Nature Communications, scientists at Lancaster University report the possibility of “glassy states” and a “super-relaxation” phenomenon, which might appear in the networks of tiny oscillators within the brain, heart and other oscillating entities.

To uncover these phenomena, they took a new approach to the solution of a set of equations proposed by the Japanese scientist Yoshiki Kuramoto in the 1970s. His theory showed it was possible in principle to predict the properties of a system as a whole from a knowledge of how oscillators interacted with each other on an individual basis.

Therefore, by looking at how the microscopic cardiac muscle cells interact we should be able to deduce whether the heart as a whole organ will contract properly and pump the blood round. Similarly, by looking at how the microscopic neurons in the brain interact, we might be able to understand the origins of whole-brain phenomena like thoughts, or dreams, or amnesia, or epileptic fits.  

Physicists Dmytro Iatsenko, Professor Peter McClintock, and Professor Aneta Stefanovska have reported a far more general solution of the Kuramoto equations than anyone has achieved previously, with some quite unexpected results.

One surprise is that the oscillators can form “glassy” states, where they adjust the tempos of their rhythms but otherwise remain uncoordinated with each other, thus giving birth to some kind of “synchronous disorder” rather like the disordered molecular structure of window glass. Furthermore and even more astonishingly, under certain circumstances the oscillators can behave in a totally independent manner despite being tightly coupled together, the phenomenon the authors call “super-relaxation”.

These results raise intriguing questions. For example, what does it mean if the neurons of your brain get into a glassy state?

Dmytro Iatsenko, the PhD student who solved the equations, admitted the results posed more questions than they answered.

“It is not fully clear yet what it might mean if, for example, this happened in the human body, but if the neurons in the brain could get into a “glassy state” there might be some strong connection with states of the mind, or possibly with disease.”

Lead scientist Professor Aneta Stefanovska said: “With populations of oscillators, the exact moment when something happens is far more important than the strength of the individual event. This new work reveals exotic changes that can happen to large-scale oscillations as a result of alterations in the relationships between the microscopic oscillators. Because oscillations occur in myriads of systems in nature and engineering, these results have broad applicability.”

Professor Peter McClintock said: “The outcome of the work opens doors to many new investigations, and will bring enhanced understanding to several seemingly quite different areas of science.”

Researchers Gain Insight into How Ion Channels Control Heart and Brain Electrical Activity

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 cell membrane 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 atrial fibrillation.

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 computational approach 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 ion channels and cell signaling mechanisms.  

“Understanding the structural mechanism of Gβγ 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 Gβγ -GIRK1 complex reveals that Gβγ 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 brain tissue, 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 Gbgsubunits 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 Gβγ-channel complex, which is the structure the team has already achieved.

A new type of nerve cell found in the brain

Scientists at Karolinska Institutet in Sweden, in collaboration with colleagues in Germany and the Netherlands, have identified a previously unknown group of nerve cells in the brain. The nerve cells regulate cardiovascular functions such as heart rhythm and blood pressure. It is hoped that the discovery, which is published in the Journal of Clinical Investigation, will be significant in the long term in the treatment of cardiovascular diseases in humans.

The scientists have managed to identify in mice a previously totally unknown group of nerve cells in the brain. These nerve cells, also known as ‘neurons’, develop in the brain with the aid of thyroid hormone, which is produced in the thyroid gland. Patients in whom the function of the thyroid gland is disturbed and who therefore produce too much or too little thyroid hormone, thus risk developing problems with these nerve cells. This in turn has an effect on the function of the heart, leading to cardiovascular disease.

It is well-known that patients with untreated hyperthyroidism (too high a production of thyroid hormone) or hypothyroidism (too low a production of thyroid hormone) often develop heart problems. It has previously been believed that this was solely a result of the hormone affecting the heart directly. The new study, however, shows that thyroid hormone also affects the heart indirectly, through the newly discovered neurons.

"This discovery opens the possibility of a completely new way of combating cardiovascular disease", says Jens Mittag, group leader at the Department of Cell and Molecular Biology at Karolinska Institutet. "If we learn how to control these neurons, we will be able to treat certain cardiovascular problems like hypertension through the brain. This is, however, still far in the future. A more immediate conclusion is that it is of utmost importance to identify and treat pregnant women with hypothyroidism, since their low level of thyroid hormone may harm the production of these neurons in the foetus, and this may in the long run cause cardiovascular disorders in the offspring."

Hypertension traced to source in brain

When the heart works too hard, the brain may be to blame, says new Cornell research that is changing how scientists look at high blood pressure (hypertension). The study, published in the Journal of Clinical Investigation in November, traces hypertension to a newfound cellular source in the brain and shows that treatments targeting this area can reverse the disease.

In what peer reviewers are calling “a new paradigm” for tackling the worldwide hypertension epidemic, this insight into its roots could give hope to the billion people it currently afflicts. Hypertension occurs when the force of blood against vessel walls grows strong enough to potentially cause such problems as heart attack, stroke and heart or kidney disease. The heart pumps harder, and often the hormone angiotensin-II (AngII) gets the pressure cooking by triggering nerve cells that constrict blood vessels.

"We knew the central nervous system orchestrates this process, and now we’ve found the conductor," said Robin Davisson, the Andrew Dickson White Professor of Molecular Physiology with a joint appointment at Cornell’s College of Veterinary Medicine and Weill Cornell Medical College.

Two-thirds of Americans have hypertension, which is the leading cause of North America’s No. 1 killer: heart disease, according to the Centers for Disease Control and Prevention.

Davisson’s lab traced neurochemical signals back to endoplasmic reticulum (ER), the protein factory and stress-management control center in every cell. If something goes wrong in a cell, the ER activates processes to adapt to the stress. Long-term ER stress can cause chronic disease, and several stressors that ER responds to have been connected to hypertension. Davisson’s lab found that high levels of AngII put stress on the ER, which responds by triggering the cascade of neural and hormonal signals that start hypertension.

But not just any cell’s ER can conduct this complex orchestra. Those that can trigger the signal cascade are clustered near the bottom of the brain in a gatelike structure called the subfornical organ (SFO). Unlike most of the brain, the SFO hangs outside a protective barrier that keeps most circulating particles from entering the brain. The SFO can interact with particles like AngII that are too big to cross through and can also communicate with the brain’s inner chambers.

This is good news for developing therapies—because the SFO sits outside the barrier, it can be reached through such normal treatment routes as pills or injections rather than riskier brain procedures. Davisson’s lab showed that treatments that inhibit ER stress in the SFO can completely stop AngII-based hypertension and lower blood pressure to normal levels.

"Our work provides the first evidence that higher levels of AngII cause ER stress in the SFO, that this causes hypertension, and that we can do something about it," said Davisson. "This finding may also suggest a role for ER stress in hypertension types that don’t involve AngII, like some spontaneous or genetic forms."

Inspired by the paradigm shift that this study has sparked, the editors of the Journal of Clinical Investigation published a commentary concluding that this discovery “opens new avenues for investigation and may lead to new therapeutic approaches for this disease.”

Guinea pig hearts beat with human cells

Damaged skin and liver can often repair themselves, but the heart rarely heals well and heart disease is the world’s leading cause of death. Research published today raises hopes for cell therapies, showing that heart muscle cells differentiated from human embryonic stem cells can integrate into existing heart muscle.

“What we have done is prove that these cells do what working heart muscles do, which is beat in sync with the rest of the heart,” says Chuck Murry, a cardiovascular biologist at the University of Washington in Seattle, who co-led the research.