# Ion Channel Transporter Interactions

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $359,791

## Abstract

ABSTRACT
Alzheimer’s disease (AD) is a neurodegenerative disorder that is increasingly prevalent in our aging populations
around the world. AD is characterized by the accumulation of Amyloid-β peptide (Aβ)-containing plaques,
neurofibrillary tangles, and also worsening cognitive deficits. Compelling evidence suggests that thiamine
homeostasis may also be changed in AD. Reduction in thiamine diphosphate (TDP) levels and abnormal
functioning of TDP-dependent key enzymes in glucose metabolism occur in the blood and brains of AD patients.
Thiamine deficiency exacerbates plaque formation and alters the metabolism of Amyloid Precursor Protein
Processing (APP) and/or Aβ in mouse models of AD; many thiamine-dependent processes are diminished in the
brains of AD patients. We previously discovered physical interaction of voltage-gated potassium (Kv) channels
with various solute transporters. We and other groups have since reported a variety of Kv channel-transporter
interactions, both in vitro and in vivo, but their potential role in AD has not been established, neither have
complexes of Kv channels with thiamine transporters been reported. We believe that Kv channel-transporter
complexes form crucial signaling hubs facilitating tight control over highly dynamic cellular processes, and that
their disruption, as we and others have shown, is associated with neurological diseases, and potentially AD.
Here, building on recent preliminary data suggestive of interactions between neuronal KCNQ channels and
thiamine transporters, we aim to test the hypothesis that KCNQ and/or KCNA Kv channels form reciprocally
regulating complexes with the human thiamine transporters THTR-1 and/or THTR-2, which are high-affinity
transporters that concentrate thiamine in cells via a downhill proton gradient. We recently demonstrated that
brains of AD patients as well as those of 5XFAD (AD model) mice express significantly reduced levels of
THTR-1 – building on prior work that demonstrated that thiamine homeostasis is altered in AD, and thiamine
deficiency exacerbates AD pathology. In addition, we also found that various Kv channels, including KCNQ2/3,
form complexes and co-localize in nodes of Ranvier with the APP early cleavage product C99, altering channel
function and in the case of KCNQ2/3 causing channel inhibition. Given these links, we hypothesize that KCNA
and KCNQ channels can form physical complexes with thiamine transporters THTR-1 and/or THTR-2 and thus
regulate one another’s function, and we will study how they change in AD. In two Specific Aims we will first
investigate in vitro existence and functional consequences of channel-transporter complex formation between
KCNA, KCNQ Kv channel α subunits and thiamine transporters THTR-1 and/or THTR-2. Next, we will investigate
possible changes in expression of neuronal KCNA and KCNQ channel isoforms, and their complex formation
with thiamine transporters THTR-1 and/or THTR-2 in different regions of the brains of AD patients a...

## Key facts

- **NIH application ID:** 10713968
- **Project number:** 3R35GM130377-05S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Geoffrey W Abbott
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $359,791
- **Award type:** 3
- **Project period:** 2019-02-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10713968

## Citation

> US National Institutes of Health, RePORTER application 10713968, Ion Channel Transporter Interactions (3R35GM130377-05S1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10713968. Licensed CC0.

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