Abstract
Mechanosensitive PIEZO ion channels are evolutionarily conserved proteins whose presence is critical for normal physiology in multicellular organisms. Here we show that, in addition to mechanical stimuli, PIEZO channels are also powerfully modulated by voltage and can even switch to a purely voltage-gated mode. Mutations that cause human diseases, such as xerocytosis, profoundly shift voltage sensitivity of PIEZO1 channels toward the resting membrane potential and strongly promote voltage gating. Voltage modulation may be explained by the presence of an inactivation gate in the pore, the opening of which is promoted by outward permeation. Older invertebrate (fly) and vertebrate (fish) PIEZO proteins are also voltage sensitive, but voltage gating is a much more prominent feature of these older channels. We propose that the voltage sensitivity of PIEZO channels is a deep property co-opted to add a regulatory mechanism for PIEZO activation in widely different cellular contexts.
Highlights
Mechanosensitive PIEZO ion channels are evolutionarily conserved proteins whose presence is critical for normal physiology in multicellular organisms
Single PIEZO1 channels may conduct more ions outward than inward, a phenomenon seen in glycine and GABAA channels[38], single channel measurements under identical conditions showed that channel outward conductance was smaller than the inward conductance (Fig. 1b)
The voltage-modulation and voltage gating of PIEZO channels appears to be a fundamental property of the channel pore and is dramatically altered by pathological mutations that cause xerocytosis
Summary
Mechanosensitive PIEZO ion channels are evolutionarily conserved proteins whose presence is critical for normal physiology in multicellular organisms. Older invertebrate (fly) and vertebrate (fish) PIEZO proteins are voltage sensitive, but voltage gating is a much more prominent feature of these older channels. Genetic ablation of either the Piezo[1] or Piezo[2] genes in mice leads to either embryonic or early post-natal lethality[1,2,10] Both mouse and human genetics have revealed roles for PIEZOmechanosensing ion channels in a variety of non-sensory cellular physiology ranging from cartilage formation by chondrocytes[11,12], epithelial sheet homeostasis[13,14], growth cone guidance[15], arterial smooth muscle remodeling[16] to blood cell shape regulation[17]. Pathological human mutations in Piezo[1] primarily weaken the inactivation gate and render the channels less sensitive to voltage modulation. We show that the biophysical properties of both invertebrate (Drosophila melanogaster) and other vertebrate (Danio rerio) PIEZOs are much more reminiscent of classical voltagegated channels than mammalian PIEZOs
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