Date of Award

5-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Cell Biology and Physiology

Research Advisor

Valeria Vásquez, PhD

Committee

Adebowale Adebiyi, PhD; Alex M. Dopico, PhD; Jonathan H. Jaggar, PhD; Gabor J. Tigyi, PhD

Keywords

Mechanosensitive ion channels;Membrane lipids;PIEZO1;PIEZO2

Abstract

In cellular physiology, the transformation of energy from mechanical cues into electrical and/or chemical signals is called mechanotransduction. This ability to sense and react to external and internal mechanical forces is essential for the survival of single cell to multicellular organisms. As such, it is no surprise that mechanotransduction appeared early in the evolutionary history of life on our planet. At the cellular level, mechanotransduction is mediated by proteins and/or protein complexes that respond to mechanical stimuli in different timescales, including but not limited to changes in membrane electric potential, Ca2+ signaling, and gene expression. Among such protein complexes, mechanosensitive ion channels stand out as the quickest mechanotransductors, as they can generate physiologically relevant responses to mechanical cues, on a millisecond timescale. Mechanosensitive ion channels are transmembrane proteins that mediate the flow of ions across the cell membrane in response to mechanical stimuli. Mechanical forces can reach, and induce a response of, mechanosensitive ion channels by propagating through the membrane and/or from extra- and intracellular tethers. The mammalian PIEZO ion channel family is comprised of two mechanosensitive non-selective cation channels, PIEZO1 and PIEZO2. These ion channels have a fundamental role in multiple normal and pathophysiological mechanisms in mammals. Loss- and gain-of-function mutations of both proteins cause disease, yet there are no pharmacological tools available to modulate their function in vivo. As a collective, the chemically diverse lipid species that comprise membranes can endow them with distinct characteristics also known as the physical properties of the bulk plasma membrane. This dissertation focuses on how lipid composition and the physical properties of the bulk plasma membrane can shape physiological responses by modulating the function of PIEZO1 and PIEZO2. Here, we use lipid profile analysis, electrophysiology, and behavioral assays to demonstrate that PIEZO1 and PIEZO2 are modulated by membrane lipids. We found that the saturated fatty acid margaric acid inhibits PIEZO2 currents by increasing its mechanical threshold for activation, whereas polyunsaturated fatty acids such as eicosapentaenoic, arachidonic, docosahexaenoic, and linoleic acids modify channel inactivation. We show that topical lotions enriched in margaric acid can be used to alter touch responses of wild-type mice in vivo. Moreover, we found that dietary interventions improve PIEZO2-associated behaviors in mouse models of neurogenetic diseases where PIEZO2 function is either up- (distal arthrogryposis type 5) or down- (Angelman syndrome) regulated. Finally, we demonstrate that PIEZO1 function is upregulated in sickle cell disease, and that fatty acids can be used to rescue this increase ex vivo. Overall, our findings demonstrate that saturated and polyunsaturated fatty acids enriched in the plasma membrane modulate mechanical responses mediated by PIEZO channels in vitro, ex vivo, and in vivo.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

0000-0001-9855-7592

DOI

10.21007/etd.cghs.2024.0656

Additional Files
2024-001-Garcia DOA.pdf (236 kB)
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