Propofol inhibits Piezo mechanosensitive channels.

Area of Science:

• Molecular Biology
• Neuroscience
• Pharmacology

Background:

• Anesthetics modulate ion channel activity, but their precise mechanisms are not fully understood.
• Propofol is a widely used anesthetic with known effects on ion channels.
• Mechanosensitive ion channels, such as Piezo channels, are implicated in cellular responses to mechanical stimuli.

Purpose of the Study:

• To investigate the interaction between propofol and human Piezo1 (hP1) and Piezo2 (hP2) mechanosensitive ion channels.
• To elucidate the specific effects of propofol on the gating and conductance of hP1 and hP2 channels.
• To determine if propofol's anesthetic action involves the inhibition of Piezo channels.

Main Methods:

• Electrophysiological recordings (outside-out, whole-cell, cell-attached) were performed on HEK293T cells expressing hP1 and hP2.
• Calcium imaging was used to assess propofol's effect on Yoda1-induced calcium influx in hP1-expressing cells.
• Dose-response relationships and kinetic parameters were analyzed to quantify propofol's inhibitory effects.

Main Results:

• Propofol inhibited hP1 currents with a dissociation constant of 51.6 μM, shifting the stimulus-response curve and increasing half-maximal pressure.
• Propofol selectively stabilized the closed state of hP1 channels, without altering conductance or slope sensitivity.
• Propofol reduced Yoda1-induced calcium influx in hP1 cells and inhibited hP2 currents by decreasing channel open probability.

Conclusions:

• Propofol directly inhibits both Piezo1 and Piezo2 mechanosensitive ion channels.
• The inhibition mechanism involves stabilizing the closed state of Piezo1 and reducing the open probability of Piezo2.
• These findings suggest that inhibition of Piezo channels may contribute to propofol's anesthetic effects.