
@article {28565,
	title = {Fluid flow modulates electrical activity in cardiac hERG potassium channels.},
	journal = {J Biol Chem},
	year = {2018},
	month = {2018 Jan 05},
	abstract = {<p>Fluid movement within the heart generates substantial shear forces, but the effect of this mechanical stress on the electrical activity of the human heart has not been examined. The fast component of the delayed rectifier potassium currents responsible for repolarization of the cardiac action potential, Ikr, is encoded by the hERG channel. Here, we exposed hERG1a channel-expressing HEK293T cells to laminar shear stress (LSS) and observed that this mechanical stress increased the whole-cell current by 30\%-40\%. LSS shifted the voltage dependence of steady-state activation of the hERG\&nbsp; channel to the hyperpolarizing direction, accelerated the time course of activation and recovery from inactivation, slowed down deactivation, and shifted the steady-state inactivation to the positive direction, all of which favored the hERG open state. In contrast, the time course of inactivation was faster, favoring the closed state. Using specific inhibitors of focal adhesion kinase (FAK), a regulator of mechano-transduction via the integrin pathway, we also found that the LSS-induced modulation of the whole-cell current depended on the integrin pathway. The hERG1b channel variant, which lacks the Per-Arnt-Sim (PAS) domain, and long QT syndrome-associated variants having point mutations in the PAS domain were unaffected by LSS, suggesting that the PAS domain in hERG1a channel may be involved in sensing mechanical shear stress. We conclude that a mechano-electric feedback pathway modulates hERG channel activity through the integrin pathway, indicating that mechanical forces in the heart influence its electrical activity.</p>
},
	issn = {1083-351X},
	doi = {10.1074/jbc.RA117.000432},
	author = {Roy, Samrat and Mathew, M K}
}
@article {3540,
	title = {The Pathogenic A116V Mutation Enhances Ion-Selective Channel Formation by Prion Protein in Membranes.},
	journal = {Biophys J},
	volume = {110},
	year = {2016},
	month = {2016 Apr 26},
	pages = {1766-76},
	abstract = {<p>Prion diseases are a group of fatal neurodegenerative disorders that afflict mammals. Misfolded and aggregated forms of the prion protein (PrP(Sc)) have been associated with many prion diseases. A transmembrane form of PrP favored by the pathogenic mutation A116V is associated with Gerstmann-Str{\"a}ussler-Scheinker syndrome, but no accumulation of PrP(Sc) is detected. However, the role of the transmembrane form of PrP in pathological processes leading to neuronal death remains unclear. This study reports that the full-length mouse PrP (moPrP) significantly increases the permeability of living cells to K(+), and forms K(+)- and Ca(2+)-selective channels in lipid membranes. Importantly, the pathogenic mutation A116V greatly increases the channel-forming capability of moPrP. The channels thus formed are impermeable to sodium and chloride ions, and are blocked by blockers of voltage-gated ion channels. Hydrogen-deuterium exchange studies coupled with mass spectrometry (HDX-MS) show that upon interaction with lipid, the central hydrophobic region (109-132) of the protein is protected against exchange, making it a good candidate for inserting into the membrane and lining the channel. HDX-MS also shows a dramatic increase in the protein-lipid stoichiometry for A116V moPrP, providing a rationale for its increased channel-forming capability. The results suggest that ion channel formation may be a possible mechanism of PrP-mediated neurodegeneration by the transmembrane forms of PrP.</p>
},
	issn = {1542-0086},
	doi = {10.1016/j.bpj.2016.03.017},
	author = {Sabareesan, Ambadi Thody and Singh, Jogender and Roy, Samrat and Udgaonkar, Jayant B and Mathew, M K}
}
