Piezo1 mechanosensitive channels: what are they and why are they important

Abstract

Mechanosensitive (MS) ion channels are integral membrane proteins which play a crucial role in fast signaling during mechanosensory transduction processes in living cells. They are ubiquitous and old in the evolutionary sense, given their presence in cells from all three kingdoms of life found on Earth, including bacterial, archaeal, and eukaryotic organisms. As molecular transducers of mechanical force, MS channels are activated by mechanical stimuli exerted on cellular membranes, upon which they rapidly and efficiently convert these stimuli into electrical, osmotic, and/or chemical intracellular signals. Most of what we know about the gating mechanisms of MS channels comes from the work carried out on bacterial channels. However, recent progress resulting from identification and structural information of eukaryotic K2P-type TREK and TRAAK as well as Piezo1 and Piezo2 MS channels has greatly contributed to our understanding of the common biophysical principles underlying the gating mechanism and evolutionary origins of these fascinating membrane proteins. Using Piezo1 channels as an example, we briefly describe in this review what we have learned about their biophysics, physiological functions, and potential roles in "mechanopathologies."

Mechanotransduction and dynamic outflow regulation in trabecular meshwork requires Piezo1 channels

“…Importantly, sustained flow and pressure stimuli may remove Piezo1 inactivation without altering the pharmacology and unitary conductance of the Piezo1 mechanocurrent (23,43,74,76). Potential inactivation-modulatory mechanisms include changes in membrane lipid composition, cytoskeletal modulation, amino acid alterations, sensitivity of N-terminal extracellular loop and the CED domains to recurrent force applications and/or presence of TMEM150c or ASIC1 proteins (73,(77)(78)(79)(80).…”

The Emerging Role of Mechanosensitive Piezo Channels in Migraine Pain

“…This is because the list of blockers of Piezo channels is limited and most of them are not specific (Table 1). Thus, there are Piezo channel inhibitors, such as the antagonist Dooku1, the blockers neurotoxin GsMTx4 and gadolinium [51]. Unfortunately, Dooku1 has a partial blocking activity in some cell types, whereas GsMTx4 or gadolinium are not specific for Piezo channels [51].…”

“…Thus, there are Piezo channel inhibitors, such as the antagonist Dooku1, the blockers neurotoxin GsMTx4 and gadolinium [51]. Unfortunately, Dooku1 has a partial blocking activity in some cell types, whereas GsMTx4 or gadolinium are not specific for Piezo channels [51]. The main issue is that even if the specific blocker of Piezo1 is found, Piezo1 channels are not limited to trigeminal neurons but expressed in other cell types such as vessels (as mentioned above).…”

“…Thus, the analgesic effect in migraine pain, can be approached either by the targeted delivery to the TGVS of the novel potent Piezo blockers, or by the inactivation of these mechanotransducers by modulators acting via changes in the lipid membrane environment. [24,25] L15-16/L19-20 regions [10] Yoda1 binding site [51] Ion channel pore [51] Changes in membrane lipid environment [16] accelerated inactivation reduced inactivation…”

2019—A year in Biophysical Reviews

“…Features of the Issue included a number of interesting Commentaries written by senior (Guck 2019;Verheyen et al 2019) and junior investigators (Steward Jr. 2019) as well as Presidents of relevant Societies (Pérez 2019). The 13 contributed Letters and Reviews address fundamental basic science questions such as the reasons for heterogeneity in cell populations (Vishwakarma and Di Russo 2019) and mechanotransduction principles in neurons and other cell types (Chighizola et al 2019;Ridone et al 2019). The review articles also present latest technological developments relating to high speed atomic force microscopy (Valotteau et al 2019) and optical trapping and microscopy techniques (Boeri et al 2019;Arbore et al 2019) along with relevant nanofabrication approaches (De Masi et al 2019).…”