# Daily Regulation of Ionic Currents

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $699,140

## Abstract

ABSTRACT
Circadian rhythms in physiology are essential for human health, and in mammals, these
rhythms are coordinated by a central circadian clock located in the suprachiasmatic
nucleus (SCN) of the hypothalamus. The SCN produces the neural code for circadian
time through time-of-day dependent modulation of the activity of various ion channels that
control action potential firing. The goal of this research is to understand the ion channel
properties, interactions, and functional consequences that set these circadian changes in
action potential activity in the SCN, focusing on two types of channels that functionally
interact during the action potential: BK K+ channels and their Ca2+ channel activators.
During the day in SCN, BK channels are activated predominantly by L-type Ca2+ channels
(LTCCs), while at night activation depends on Ryanodine Receptors (RyRs). How this
switch between the two Ca2+ channel subtypes occurs is not yet known but has important
implications during the action potential for any cell where BK channels utilize multiple
Ca2+ sources. The proposed studies test the hypothesis that modulation of BK activity via
specific Ca2+ channel coupling alters the contribution of BK channels to the action
potential. The circadian consequences of this altering this functional coupling will then
be probed with Ca2+ channel mutations, as well as BK channel mutations associated with
the neurological disorder KCNMA1-linked channelopathy. Our specific aims are to: (1)
Determine the key subunits and the physical and functional interactions between BK and
Ca2+ channels that regulate firing in day and night in SCN using biochemistry and
electrophysiology. The consequences of disrupting these interactions on circadian
rhythm will be assessed in the SCN circuit and circadian behavioral outputs, and (2)
Determine how pathogenic KCNMA1 patient mutations that alter BK channel activity
affect BK current, action potential firing, and the circadian aspects of sleep and seizure
as a result of their interactions with the respective LTCC and RyR Ca2+ channels. Using
the SCN as a model, the outcome of the proposed studies will reveal how specific ion
channel partnerships work together during the action potential to control firing, and how
and how dysregulation of their properties and interactions contribute to circadian, sleep,
and seizure disorder.

## Key facts

- **NIH application ID:** 10148482
- **Project number:** 2R01HL102758-11
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Andrea L Meredith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $699,140
- **Award type:** 2
- **Project period:** 2010-04-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148482

## Citation

> US National Institutes of Health, RePORTER application 10148482, Daily Regulation of Ionic Currents (2R01HL102758-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10148482. Licensed CC0.

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