Tubular Renal Epithelial Cells are Active Mechanobiological Water Pumps

Abstract

Ketamine, a widely used anesthetic, is currently under renewed inquiry for its rapid and sustained antidepressant effects at sub anesthetic doses. Ketamine exerts its effects on the central nervous system (CNS) by blocking open Nmethyl-D-aspartate (NMDA) receptors with IC 50 = 1.0 uM. This overall effect is modulated regionally and temporally by dynamic variations in extracellular pH at synapses. An increase in extracellular proton concentrations decrease NMDA receptor open probability (Po) with IC 50 = 7.0 in an isoform dependent manner, and protonated forms of ketamine are more potent blockers of NMDA receptors. In an effort to separate the effects of proton inhibition and ketamine block on channel activity, we used GluN1-1b containing NMDA receptors with reduced proton sensitivity (IC 50 = 6.7) expressed in HEK293 cells and quantified the receptors' activation mechanism with kinetic modelling from on-cell single channel recordings. With this approach, we estimated rate constants for channel gating and for ketamine association and dissociation at pH 6.8, 7.2, and 7.6. The activation mechanism of protonated GluN1-1a and GluN1-1b isoforms were indistinguishable. As expected, ketamine reduced the channel mean open time with no changes in unitary conductance. Furthermore, ketamine increased the mean closed time and reduced the number of open components. These results quantify the distinct effects of protons and ketamine on NMDA receptor activity, and serve to better understand the complex modulatory actions of pharmacologic interventions.

Light-induced nanoscale deformation in azobenzene thin film triggers rapid intracellular Ca2+increase via mechanosensitive cation channels

“…Such heterogeneity has been reported for example in cell responses to stretch (Latorre et al 2018) and compression (Peussa et al 2022). Also, MDCK II cells cultured as monolayers, when matured, form fluid-filled dome structures into the monolayer (Choudhury et al 2022), which may render some cells unreachable by photostimulation.…”

Coordination of LMO7 with FAK Sustains Epithelial Integrity in Renal Epithelia Exposed to Osmotic Pressure

“…The epithelial barrier is the physiological interface between the external and internal milieu of the body 43,44 . This physiological interface in the kidney comprises a renal tubular epithelial layer 44 .…”

“…The epithelial barrier is the physiological interface between the external and internal milieu of the body 43,44 . This physiological interface in the kidney comprises a renal tubular epithelial layer 44 . Renal tubular epithelial sheets in the kidney are not only structural isolators but also physiologically regulate body fluid and electrolyte homeostasis 44,45 .…”

“…This physiological interface in the kidney comprises a renal tubular epithelial layer 44 . Renal tubular epithelial sheets in the kidney are not only structural isolators but also physiologically regulate body fluid and electrolyte homeostasis 44,45 . Cells in the REB frequently exhibit osmotic dynamics 2 .…”