Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

On...off...on...off... The circuitry of insulin-releasing cells

10.12.2010
Johns Hopkins researchers uncover potential inroad to diabetes treatment

A myriad of inputs that report on a body’s health bombard pancreatic beta cells continuously, and these cells must consider all signals and “decide” when and how much insulin to release to maintain balance in blood sugar, for example.

Reporting in Nature Chemical Biology last month, researchers at the Johns Hopkins University School of Medicine have teased out how these cells interpret incoming signals and find that three proteins relay signals similar to an electrical circuit.

“Pancreatic beta cells are influenced by hormonal, metabolic and electrical signals and something must be integrating all of these inputs to determine how to generate the cell’s output,” says Jin Zhang, Ph.D., an associate professor of pharmacology and molecular sciences at Johns Hopkins. “We have discovered a tunable circuit that may control the behavior of the cell.”

According to Zhang, typically PKA (protein kinase A) acts as a switch and turns on and does what it needs to do until it’s done and turns off. The team initially noticed that PKA was switching on and off while observing fluorescently tagged live cells under a microscope. “It was so interesting and uncharacteristic we had to study it further,” says Zhang.

So the team started by again recording video of live cells over the course of an hour. They took advantage of so-called biosensors that they engineered, which are protein tags that glow one color when turned off and another color when turned on. By inserting a PKA biosensor into these cells, they were able to see when PKA was turned off and on. They found that PKA does turn on and off in regular intervals—about three cycles every 10 minutes.

“We already knew that calcium levels in these cells oscillate and this controls the release of insulin,” says Zhang. “So we were curious to see how the PKA oscillation we observed was linked to calcium.”

Using a dye that changes color when calcium levels are high, the team again observed live cells and found that PKA oscillations and calcium oscillations were in register with each other—every time PKA turned on, calcium peaked a short while later, and PKA would turn off almost immediately, overlapping with a decrease in calcium. “This too was surprising because turning off PKA in other types of cells normally is slow, on the order of tens of minutes, but in these cells it was fast, on the order of just a few minutes,” says Zhang.

The team then turned to colleagues in biomedical engineering at the Johns Hopkins Whiting School of Engineering to build a mathematical model of this circuit to better study and predict how these oscillating signals are used in a cell. Culling everything that is known about PKA, calcium and another chemical in the cell that affects PKA activity, Levchenko’s team came up with a model where all three components are closely linked by cross-talk so that the oscillatory behavior of each was determined by the activity of the other two. “Human engineers have figured out a long time ago that oscillating signals can carry more information than the steady ones, and it was fascinating to see that cells might have arrived at the same solution, too,” says Andre Levchenko, Ph.D., an associate professor of biomedical engineering at Johns Hopkins.

The model predicted that blocking PKA activity would stop calcium levels from oscillating as well; so the team treated cells with a chemical that blocks PKA and found that indeed, calcium levels stopped changing. The model also predicted that increasing PKA activity would change the frequency of calcium oscillations; again, adding a different chemical that increases PKA activity in turn increased calcium oscillation frequency. “The mathematical model enabled us to do more informed experiments and uncover even more about the activity of these molecules in the cell,” says Zhang.

So what does this all mean? According to Zhang and Levchenko, they may have come up with an explanation for a long-standing mystery in the field. Low PKA oscillation frequency tunes PKA to act locally, in the immediate region where it is anchored in the cell. And high PKA oscillation frequency tunes PKA to work more globally throughout the cell, to generate a different response.

The discovery of PKA’s oscillating activity and its involvement in this protein circuit in pancreatic beta cells is intriguing to Zhang, who hopes that this finding can lead to repairing deficient cells in treating diabetes. “This type of circuit-like control also may be more widespread among different kinds of cells,” says Zhang. “We’re eager to see what our new biosensors can teach us.”

This study was funded by the National Institutes of Health.

Authors on the paper are Qiang Ni, Ambhighainath Ganesan, Nwe-Nwe Aye-Han, Xinxin Gao, Michael Allen, Andre Levchenko and Jin Zhang, all of Johns Hopkins.

On the Web:
Nature Chemical Biology: http://www.nature.com/nchembio/index.html
Jin Zhang: http://neuroscience.jhu.edu/JinZhang.php
Andre Levchenko: http://www.bme.jhu.edu/people/primary.php?id=391
Media Contacts:
Audrey Huang; 410-614-5105; audrey@jhmi.edu
Vanessa McMains; 410-502-9410; vmcmain1@jhmi.edu
Maryalice Yakutchik; 443-287-2251; myakutc1@jhmi.edu

Vanessa McMains | EurekAlert!
Further information:
http://www.jhmi.edu

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>