# Ion channel regulation by heterogeneous membranes

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $261,660

## Abstract

Ion channels are membrane bound proteins that mediate fast neural dynamics by selectively controlling the
flow of charged ions across membranes. Most channels are embedded within compositionally complex
neuronal membranes, whose detailed composition play important roles in regulating channel functions.
Membranes can regulate channels directly, through the binding of specific components to sites within channel
structures, or indirectly, by impacting the biophysical and biochemical processes evolved to regulate channel
functions in their native environment. A mechanistic understanding of how membrane composition impacts
channel functions is vital because changes in neuronal membrane composition are associated with normal
development and neurological disease. The goal of the proposed studies is to test three distinct mechanisms
through which compositionally complex membranes regulate channel function. The working hypothesis,
supported by past collaborative work of the Pl and Col, is that some channel functions are regulated by
emergent properties of their embedding membranes that occur because these membranes are heterogeneous.
Guided by extensive preliminary data, three specific aims will be pursued: 1) Measure the functional coupling
of channel states to membrane domains, 2) Establish how membrane domains impact the binding of allosteric
regulators, and 3) Identify the roles of membrane domains within the broader regulatory environment of
neurons. The first aim experimentally tests a minimal model positing that single channel functions are
allosterically regulated by domains within embedding membranes through tuning the availability of preferred
local lipid environments. The second aim explores how the chemical potential of known allosteric regulators
such as cholesterol and phosphoinositide lipids are impacted by the same thermodynamic parameters that
control properties of membrane domains. The third aim investigates how membrane domains impact the
sorting of enzymes that participate in protein palmitoylation and tyrosine phosphorylation regulatory pathways
occurring at neuronal synapses. Experimental approaches draw on the PIs expertise using quantitative super-resolution
fluorescence localization microscopy techniques and are combined with functional studies, theory,
and simulation to test and refine mechanistic models of isolated and collective channel functions. The
proposed work is innovative because it applies predictive models of membrane organization that are novel to
both the channel and membrane domain communities. A broadly applicable framework for describing how
domains modulate channel functions will drive advances in neuroscience by providing new insights into the
functional basis for membrane changes with development and neurological disease, will motivate more
effective and targeted treatments for neurological disease, and will connect the molecular-scale behaviors of
channels to larger questions in neuroscience through the collec...

## Key facts

- **NIH application ID:** 10016343
- **Project number:** 5R01GM129347-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Sarah L Veatch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $261,660
- **Award type:** 5
- **Project period:** 2019-09-13 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10016343

## Citation

> US National Institutes of Health, RePORTER application 10016343, Ion channel regulation by heterogeneous membranes (5R01GM129347-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10016343. Licensed CC0.

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