Navigation Links
New Scripps Research and GNF study helps explain how we can sense temperatures

LA JOLLA, CA April 22, 2010 Scientists at The Scripps Research Institute and the Genomics Institute of the Novartis Research Foundation (GNF) have shed new light on the molecular mechanism that enables us to sense temperature, such as the heat from a sizzling stove. In addition to contributing to our knowledge of basic biology, the findings could one day lead to new therapies for conditions such as acute or chronic inflammatory pain.

The study, which was led by Scripps Research and GNF Professor Ardem Patapoutian, was published in an advance, online edition of the journal Nature Neuroscience on April 22, 2010.

To better understand temperature sensation, the team focused on a protein called TRPV1, which is a member of a small family of proteins known to enable temperature sensation, and is involved in inflammation and the communication of pain to the brain. After producing thousands of mutants of this protein, the scientists were able to identify a region of the protein that enabled temperature sensitivity and to detail some of the molecular mechanisms at work in the molecule.

"Ever since the discovery of these proteins, it has been an outstanding question how they can be activated by temperatures," said Research Associate Jrg Grandl, a member of the Patapoutian lab and first author of the paper. "The new study addresses this question."

"Because our ability to sense temperature is closely linked to our ability to sense pain, some of these ion channels are considered targets to treat chronic inflammatory and neuropathic pain indications," said Patapoutian. "Understanding these proteins could be crucial in designing future drugs that can either activate or block them."

Hot and Cold

Humans and other vertebrate animals use specialized sensory neurons to detect temperature, pressure, and other physical stimuli on the skin. These neurons are located in the spinal column and are connected to the skin and organs through long extensions known as axons.

On the surface of these axons are ion channel (pore-forming) proteins, which span the axon's membrane, connecting the inside with the outside. Some of these ion channels act like temperature receptors or "molecular thermometers" by opening and closing according to the temperature. At a particular temperature, the receptors open. This allows an influx of ions into the neuronal processes, and this electrical signal is relayed through the neuron to the brain.

The existence of specialized hot- and cold-neurons had been known for years, but the molecules that actually sense the temperatures and signal back to the neuron through the axon were a mystery. That changed in 1997 when a group cloned TRPV1, which is a type of transient receptor potential (TRP) channel. TRPV1, an ion channel, opens when it senses hot temperaturesabove 42 C (108 F).

That discovery opened the floodgates for identifying other temperature-detecting proteins. Within a few years, several laboratoriesincluding Patapoutian'shad identified additional temperature-detecting proteins and confirmed that mammals used them to detect temperature.

But how the proteins achieved their temperature-sensing ability remained a mystery. While scientists in the field knew in much detail how ion channels were activated by chemicals or voltage signals, the molecular structures required for temperature activation remained unknown.

Two competing theories were advanced to explain the activation of ion channels in response to temperature. Drawing on the proteins' similarity to voltage-gated potassium channels, the first theory posited that TRP channels are generating temperature sensitivity because the energies required for voltage activation are very finely tuned. In contrast, the second theory proposed that these channels have a modular structure and therefore possess a specific domain that enables them to be activated by temperature and postulated the existence of a 'temperature-sensor domain'.

Point by Point

To gain insight into how these ion channels achieve their temperature sensitivity, in the new study the scientists conducted studies of TRPV1, which was not only the first TRP to be discovered but is also the best understood. A previous study in the lab had focused on a related, warm-activated ion channel, TPRV3, but since the biophysics of this molecule is complicated, the team was unable to tease apart its mechanisms.

Using mutagenesis techniques, for the new study the scientists first generated some 8,500 mutants of TRPV1. Then, working with the high throughput equipment available at GNF, the team performed an unbiased screen of these compounds to identify mutations of interest.

"We were looking for mutations in these proteins that would only change the temperature sensitivity of these channels, but would not affect any of the other activation mechanisms," said Grandl. "We were looking for single-point mutations [changes of a single amino acid] where the channel still functioned normally in response to capsacin (the active ingredient in chili peppers) or pH, but not to temperature."

Indeed, the team found a number of these mutations that affected the molecule's sensitivity to temperature, but not to other cues. Interestingly, the mutations were clustered in one area of the protein, the outer pore region, which provides further support to the existence of the predicted 'temperature-sensor domain'.

Next, with these mutant versions of TRPV1 in hand, the scientists examined what had changed in the molecule to disrupt temperature sensitivity.

In findings new to the field, the team discovered that TRPV1 has two ways of opening its channelfor a brief time, opening for only for a millisecond before returning to its closed resting state, and for a relatively long time, opening for about 10 milliseconds. The team found that the mutations disrupting temperature sensitivity interfered with the long channel openings, but not the short ones.

"This study suggests a potential molecular mechanism that generates extreme temperature sensitivity from two mildly temperature sensitive steps," said Grandl. The team postulates that by stabilizing the open state, the pore domain contributes to thermosensitivity of TRPV1. "We now have a novel working model of how Nature could have evolved such exquisite temperature sensitivity, a hypothesis that can be tested in future work."


Contact: Keith McKeown
Scripps Research Institute

Related biology news :

1. Scripps Research scientists reveal how genetic mutations may cause type 1 diabetes
2. New nano-tool synthesized at Scripps Research Institute
3. Scripps Research scientists solve mystery of fragile stem cells
4. Scripps research team reveals how an old drug could have a new use for treating river blindness
5. Scripps Research scientists find two compounds that lay the foundation for a new class of AIDS drug
6. Scripps Research scientists create new way to screen libraries of 10 million or more compounds
7. Scripps Research team wins global race to achieve landmark synthesis of perplexing natural product
8. Scripps Florida scientists show lifeless prions capable of evolutionary change and adaptation
9. Scripps research team develops technique to determine ethnic origin of stem cell lines
10. Scripps Research scientists crack mystery of proteins dual function
11. Scripps Research team uncovers chemical basis for extra quality control in protein production
Post Your Comments:
(Date:5/3/2016)... , May 3, 2016  Neurotechnology, a ... the MegaMatcher Automated Biometric Identification System (ABIS) ... large-scale multi-biometric projects. MegaMatcher ABIS can process multiple ... using any combination of fingerprint, face or iris ... MegaMatcher SDK and MegaMatcher Accelerator , ...
(Date:4/26/2016)... 2016 Research and Markets has ... Market 2016-2020"  report to their offering.  , ,     ... The analysts forecast the global multimodal biometrics market ... the period 2016-2020.  Multimodal biometrics is ... as the healthcare, BFSI, transportation, automotive, and government ...
(Date:4/14/2016)... , April 14, 2016 ... and Malware Detection, today announced the appointment of ... the new role. Goldwerger,s leadership appointment comes ... the heels of the deployment of its platform at ... behavioral biometric technology, which discerns unique cognitive and physiological ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... ... , ... STACS DNA Inc., the sample tracking software company, today announced that ... joined STACS DNA as a Field Application Specialist. , “I am thrilled that ... of STACS DNA. “In further expanding our capacity as a scientific integrator, Hays brings ...
(Date:6/23/2016)... 23, 2016 Apellis Pharmaceuticals, Inc. today ... trials of its complement C3 inhibitor, APL-2. The ... ascending dose studies designed to assess the safety, ... injection in healthy adult volunteers. Forty ... a single dose (ranging from 45 to 1,440mg) ...
(Date:6/23/2016)... , June 23, 2016 ... Hematology Review, 2016;12(1):22-8 ... , the peer-reviewed journal from touchONCOLOGY, Andrew ... escalating cost of cancer care is placing an ... result of expensive biologic therapies. With the patents ...
(Date:6/23/2016)... ... 23, 2016 , ... ClinCapture, the only free validated electronic ... showcase its product’s latest features from June 26 to June 30, 2016 for ... Disrupting Clinical Trials in The Cloud during the conference. DIA (Drug Information ...
Breaking Biology Technology: