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Cooperation between pain receptors and transducers in cold pain signalling

Primary Supervisor: Dr Xuming Zhang, School of Life Sciences

Secondary supervisor: Dr Mark Wall

PhD project title: Cooperation between pain receptors and transducers in cold pain signaling

University of Registration: University of Warwick

Project outline:

Acute pain is beneficial to survival by triggering rapid avoiding responses to dangerous and painful stimuli in the environment such as noxious cold and chemicals. These painful stimuli are first detected by pain receptors on sensory nerve endings and then converted into nerve signals (action potential) through a cooperation between pain receptors and voltage-gated sodium channels. The generated pain signals are then transduced to the spinal cord and brain where they are processed and decoded, leading to the perception of pain. Many important pain receptors have been discovered in the last 25 years. Notably, discovery of receptors for temperatures and touch has led to the Nobel Prize award in Physiology and Medicine 2021.

Despite the breakthrough and progress, we still do not know how noxious cold temperatures are sensed and transduced. The transient receptor potential ankyrin 1 (TRPA1) ion channels have been proposed to play a role, though it remains highly controversial. It now becomes clear that TRPA1 alone is not sufficient to transduce noxious cold signaling and may require additional partners to fulfil the task. Interestingly, the voltage-gated Na+ (Nav) channel Nav1.8 is critical to extreme cold signaling because painful responses to extreme cold (-5°C) are absent in Nav1.8 lacking animals, though responses to other ranges of noxious cold (above 0°C) are intact. It suggests that Nav1.8 alone is inadequate to account for all aspects of noxious cold signaling, either.

Interestingly, we have recently made a discovery that a scaffolding protein is essential to noxious cold signaling, deletion of the scaffolding protein dramatically blunted noxious cold sensation and cold pain. In this project, we will investigate the molecular and cellular mechanisms of noxious cold sensation mediated by the scaffold protein. We will examine the role of the scaffolding protein in the regulation of membrane trafficking and function of TRPA1 and Nav1.8 channels, respectively. We will then investigate the role of the scaffold protein in their functional coupling and the role of this coupling in the generation of action potentials and noxious cold signaling. We will address this topical yet unresolved question using interdisciplinary approaches including electrophysiology, cell culture, live cell Ca2+imaging, animal behaviour, molecular biology, gene manipulations and transfections, immunocytochemistry, and image analysis.

You will be able to engage our cutting-edge research in two laboratories with complementary expertise and will have excellent opportunities to learn multi-disciplinary knowledge (neuroscience, pharmacology, molecular biology and imaging) and a range of interdisciplinary techniques in a vibrant and stimulating environment.

References:

  1. MacDonald DI et al, Molecular mechanisms of cold pain. Neurobiology of Pain, 2020.
  2. Kwan KY, et al, Burning cold: involvement of TRPA1 in noxious cold sensation. J Gen Physiol 2009, 133 (3): 251-256.

BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and behaviour

Techniques that will be undertaken during the project:

  • Electrophysiology
  • Cell culture
  • Live cell Ca2+ imaging
  • Animal behaviour
  • Molecular biology
  • qPCR, gene manipulations and transfections
  • Immunocytochemistry
  • Image analysis

Contact: Dr Xuming Zhang, University of Warwick