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Grant Lab

TRPV4 as a sensorimotor regulator

Since the discovery of the mechanically sensitive cation channel Transient Receptor Potential Vanilloid 4 (TRPV4) in 2000 it has been implicated in a wide variety of physiological and pathophysiological processes. These range from control of body fluid homeostasis to sensation of noxious pressure. A major site of TRPV4 expression is in the epithelial and endothelial cells that form organ surfaces throughout the body. Activation of TRPV4 in these cells by mechanical and chemical stimuli indirectly regulates the activity of other nearby cells, such as smooth muscle cells and neurons. My research is focussed on understanding these interactions and investigating how they are altered in disease states

Role of non-neuronal TRPV4 in somatic sensation

Mice lacking TRPV4 show reduced sensitivity to mechanical and heat pain under certain circumstances. Several studies of TRPV4 in pain conditions have proposed that it is expressed by sensory neurons within the peripheral
nervous system. We have been unable to find any evidence for functional TRPV4 in cultured mouse dorsal root ganglion sensory neurons (Alexander et al., 2013). However, TRPV4 is highly expressed by keratinocytes, and can
stimulate release of ATP, potentially activating adjacent sensory neurons. We are currently studying how TRPV4 activity in keratinocytes can be modulated, and establishing co-cultures of keratinocytes with sensory neurons to allow intercellular communication between them to be studied.

Contribution of odontoblast TRPV4 and TRPA1 to dental pain

The Hydrodynamic Theory of dental pain, developed to explain the differences between pain sensation in the tooth and other areas of the body, postulates that dental pain is caused by fluid movement within the closed space of the tooth being detected by trigeminal sensory nerves. Based on their location, cellular anatomy and expression of mechanosensitive ion channels the odontoblasts, cells that secrete the mineralised dentine of the tooth, have
also been proposed to play a sensory role. We have identified TRPV4 and TRPA1 in cultured human odontoblasts, and are currently investigating how the activity of these channels can be modulated and how they could communicate
with sensory neurons

Regulation of visceral smooth muscle contraction by TRPV4

The urothelium, the epithelial lining of the bladder, strongly expresses TRPV4, which plays an important role in detection of stretch during bladder filling. Loss of TRPV4 causes the bladder to overfill, and leak urine. We identified an increase in muscarinic contractions in bladders from mice with TRPV4 deletion, suggesting the presence of a urothelial mechanism dependent on TRPV4 activation that inhibits smooth muscle contraction. We are investigating this interaction in more detail, to see how it can be altered physiologically and in pathological conditions to affect bladder function.  

Image 1:    Ca2+ fluorimetry with Fura-2 in cultured mouse DRG neurons  

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Image 2:    Concentration-dependent increase in internal calcium concentration in cultured human odontoblasts exposed to the TRPV4 agonist GSK1016790A, and inhibition by the TRPV4 antagonist HC067047.

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Image 3:      A Western blot showing prominent expression of TRPV4 in mouse bladder urothelium (U), but not in the underlying muscle layer (M)

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