# Chemical biology of voltage-gated cation channels

> **NIH NIH R35** · UNIVERSITY OF IOWA · 2024 · $110,933

## Abstract

Voltage-gated ion channels shape electrical signaling in the excitable cells of nerve and muscle. Sodium (NaV)
and calcium channels (CaV) drive membrane depolarization and activate second messenger pathways via gated
cellular entry of their namesake ions. In skeletal and cardiac cells, CaV channels trigger muscle contraction.
Voltage-gated potassium channels (KV) allow the release of potassium ions from within the cell to drive
membrane repolarization. In concert, these channels provide the molecular foundation for thought, perception,
and contraction. High-resolution protein structures of human voltage-gated channels are now providing the first
glimpses of the types of poses they may adopt in cellular environments. However, understanding the ultimate
link between how these proteins look and how they support physiological mechanisms is a major challenge that
will require innovative approaches. For one, transmembrane voltage is absent in a structural experiment thus
depicting voltage-gated channels in an essentially non-physiological environment. We are therefore developing
photochemical `stapling' approaches to covalently trap high-value protein conformations in live cell membranes
prior to purification for structural determination. Further, we have begun to identify mechanisms of channel
function by introducing modified chemistries at the peptide backbone in the transmembrane segments that form
voltage-sensors and channel gates. In cellular settings, ion channels are also critical amplifiers of transduction
pathways. During the fight-or-fight response, for instance, the near instantaneous phosphorylation of CaV1.2
channels results in faster and sustained channel opening, leading to a more forceful and rapid heart rate. Yet
the absolute speed and complexity of the process is a challenge to experimentally parse individual molecular
events that result in channel gating modifications. We describe newly validated methods that enable light
controlled, site-specific phosphorylation, for the careful deconstruction and identification of key steps and players
is this process. Lastly, CaV channels can be therapeutically inhibited to manage pain, epilepsy, arrythmia, high
blood pressure, and alternatively, activated to treat heart failure. Surprisingly, both of these effects (channel
activation and inactivation) can be elicited by medicines binding a common extracellular binding site on the
channel. Conversely, unintended blockade of cardiac hERG potassium channels by otherwise useful
therapeutics cause 90% of drug induced long-QT syndrome, a potentially lethal cardiac arrhythmia. All of these
chemical binding events rely on aromatic rich binding sites formed by the side-chains of phenylalanine and
tyrosine residues in CaV and hERG channels. To better understand these chemical interactions, we have
developed a high-resolution method that allows for energetic and nuanced dissection of these aromatics within
the CaV and KV drug binding aromatic boxes in the e...

## Key facts

- **NIH application ID:** 11099454
- **Project number:** 3R35GM148239-02S1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Christopher A Ahern
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $110,933
- **Award type:** 3
- **Project period:** 2023-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11099454

## Citation

> US National Institutes of Health, RePORTER application 11099454, Chemical biology of voltage-gated cation channels (3R35GM148239-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11099454. Licensed CC0.

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