We are interested in the molecular and cellular mechanisms of somatosensory biology and pain. Noxious stimuli such as extreme heat, cold and damaging mechanical stimuli cause acute pain by direct activation of nociceptors on sensory nerve endings. Many ion channels and receptors have been identified to be responsible for direct detection of these stimuli leading to distinct sensory modalities. For example, TRPV1 channels detect heat, TRPM8 channels sense cooling and TRPA1 detects noxious cold. Altered function and regulation of these key TRP ion channels are one of the major mechanisms of acute and chronic pain. It is therefore not surprising that TRP channels have become the highly sought-after drug targets for combating pathological pain.

The first line of our research is to understand the modulation of TRP channels by inflammatory agents and signaling messengers. Towards this aim, we have found that the heat sensitivity of TRPV1 channels is governed by a network of signalling messengers including Src tyrosine kinase (Zhang X et al, EMBO J 2005), PKA, PKC and PP2B subjected to further coordination by the scaffolding protein AKAP79/150 (Zhang X et al, Neuron 2008; Li L et al, J Neurosci. 2014). We also found an unconventional mechanism by which the cold sensitivity of TRPM8 channels is directly gated by Galpha q protein subunit per se independently of the downstream signaling messengers activated by Galpha q (Zhang X et al, Nat. Cell Biol 2012; Cell Reports 2019). These uncovered mechanisms significantly enhanced our understanding of pain and provided routes for drug discovery for pain therapy.

The second aspect of our ongoing research is to understand the modulation of voltage-gated Na⁺, Ca²⁺ and K⁺ channels and their contributions to chronic pain. Pain signals are generated as a consequence of activation of nociceptive channels. However, transmission of generated pain signals to the brain depends on the concerted actions of voltage-gated Na⁺, Ca²⁺ and K⁺ channels that dictate membrane excitability of sensory neurons. The importance of these channels in pain is exemplified by the fact that gain-of-function mutants are associated with pain hypersensitivity while loss-of-function mutants leading to congenital insensitivity to pain.

Thirdly, we investigate the functional coupling between TRP channels and voltage-gated Na⁺, Ca²⁺ and K⁺ channels. Pain signal generation and transmission are not separate but are integrated and interlinked processes. We study functional interactions between these channels and the signaling messengers involved in this process. We interrogate how ion channel coupling contributes to different sensory and pain modalities.

Our ambitions are to identify the targets critical to pain facilitating the development of efficacious analgesics. We use a combination of molecular biology, protein biochemistry, electrophysiology, histology, cell culture, qPCR, Ca²⁺ imaging, pain models and behaviours to tackle our research questions.