Identification and functional characterization of Piezo2-multiprotein complexes involved in mechanotransduction

• Applicants: David Gomez Varela, Ph.D.; Professorin Dr. Manuela Schmidt
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 282480207

Our sensory universe is rich. From a gentle touch of a mother to the painful perception of stepping on a nail, our ability to perceive and encode such different inputs is critical for survival. However, mechanosensation, the ability to perceive mechanical stimuli, remains the least understood sense in vertebrates. At the level of the vertebrate somatosensory system our sense of touch and the detection of pain rely on the activation of specialized mechanosensitive neurons which innervate the skin and internal organs. These neurons are able to detect mechanical stimuli due to the expression of distinct mechanosensitive proteins, among them mechanically activated ion channels. Mechanical stimulation mediates ion channel gating which results in ion flux across membranes, thus representing the first step in the conversion of mechanical stimuli into an electrical code. Despite intensive research efforts the molecular identity of these mechanically gated ion channels in the vertebrate somatosensory system is largely unknown. Among the few considered candidates, the very recently discovered Piezo1 and Piezo2 channels represent a novel bona fide class of mechanosensitive ion channels. In mice Piezo2 is abundantly expressed in somatosensory neurons where it mediates rapidly adapting mechanocurrents. Accordingly, in vivo knock down of Piezo2 affects touch responses in mice. The consequences of Piezo2 activation are likely to depend critically on associated proteins that regulate Piezo2 activity, on the type of neuron where these proteins are expressed and also on the subcellular microdomains where they are located. All these aspects are currently unknown. We propose to identify and study Piezo2 associated protein complexes involved in mechanosensation in sensory neurons of mice. To this end, we will combine quantitative mass spectrometry techniques, mouse behavioral pain paradigms, electrophysiology and in vivo manipulation of protein expression levels. We expect to identify novel molecular components of the mechanosensitive apparatus in somatosensory neurons and thereby contribute to our understanding of somatosensory mechanosensation in vertebrates.

• DFG Programme: Research Grants