Sensing a breakthrough….


Touch is one of the five key senses that allow humans to effectively interact with their external environment. It’s also important for proprioception, the body’s sensing of the relative positioning of neighbouring body parts and the strength of effort being employed in movement. The ability to sense force, scientifically termed mechanosensation, has been the subject of much scientific endeavour. Despite this our understanding of this fundamental process at the molecular level has until recently been lacking. Electrical changes in cells and tissues in response to mechanical deformation have been widely reported and characterised, but it wasn’t until 2010 that Ardem Patapoutian and colleagues identified the Piezo proteins (Coste et al 2010). This small family (2 members at present) of unique structural proteins (Piezo1 & Piezo2) give rise to mechanically activated cation channels.

Since their discovery there have been a number of reports of human diseases arising from genetic mutations in the Piezo channels (table 1). These Piezo associated channelopathies result in significant and severe musculoskeletal phenotypes but have surprisingly not been associated with any defect in touch or proprioception.

Author, year Channel Disease Description
Zarychanski et al 2012;

Bae et al; 2013

Piezo1 Hereditary xerocytosis Hemolytic anaemia characterised by erythrocyte dehydration; gain of function (exhibit slowed inactivation)
Lukacs et al 2015 Piezo1 Congenital lymphatic dysplasia Loss of function (reduced channel surface expression levels)
Coste et al 2013

McMillin et al 2014

Okubo et al 2015

Piezo2 Distal arthrogryposis type 3 & type 5 Bone developmental malformations (cleft palate) and contractures; gain of function (inactivation changes)

Table 1: recent papers describing human mutations in Piezo channels

However two recent papers (Chesler et al 2016; Mahmud et al 2016) have described for the first time loss of function mutations in Piezo2. These patients, in common with the Piezo2 gain of function mutations, have skeletal abnormalities including contractures. However both papers report a loss of certain elements of both touch sensation and proprioception consistent with Piezo2 being key to these processes. Specifically patients had selective loss of discriminative touch perception parameters (touch, pressure and vibration) but responded to types of gentle stimulation (slow brushing) on hairy skin. In contrast non-hairy skin (glabrous skin) did exhibit a sensory defect. Affected patients also displayed profoundly decreased proprioception leading to ataxia (disorder of balance and co-ordination) and dysmetria (inability to judge distance or scale characterised by undershoot or overshoot with position of limbs).

These papers have provided clinical insight into touch and proprioception and a key role for Piezo2.  Whether Piezo2 or its close family member, Piezo1, can be modulated to deliver therapeutic benefit remains to be seen. However the discovery of the first low molecular weight modulator of Piezo1, Yoda1 was recently published (Syeda et al 2015), potentially lowering this hurdle. This compound, the output of a large high throughput screening campaign, is an agonist of both human and mouse Piezo1 and optimistically will help clarify further the role of these enigmatic channels in human health and disease

Figure 1: chemical structure of Yoda1

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Blog written by Martin Gosling

References:

Chesler et al (2016) The role of PIEZO2 in human mechanosensation. New England Journal of Medicine doi: 10.1056/NEJMoa1602812

Mahmud et al (2016) Loss of the proprioception and touch sensation channel PIEZO2 in sibling with a progressive form of contractures. Clinical Genetics doi: 10.1111/cge.12850

Syeda et al (2015) Chemical activation of the mechanotransduction channel Piezo1. ELife doi: 10.7554/eLife.07369.

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