# Pregnenolone constricts cerebral vascular arteries through the direct modulation of BK ion channels

> **NIH NIH F31** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2021 · $46,036

## Abstract

In mammals, the Ca2+- and voltage-gated K+ channels of large conductance (BK) consist of a
tetramer of channel-forming α and regulatory subunits. BK β1 subunits show localized
expression in smooth muscle (SM) and increase the Ca2+-sensitivity of BK, allowing this channel
to oppose depolarization-induced Ca2+ influx and limit SM contraction. Pregnenolone (PREG) is
a local and circulating neurosteroid involved in modulating neuronal firing, growth and
differentiation. Studies suggest that depression, anxiety, and Alzheimer progression could be
modified through optimization of PREG levels. PREG effects on the brain have been primarily
attributed to PREG actions on the neurons themselves. However, PREG is a vasoactive agent
in peripheral arteries, exerting its effect via steroid receptors. Despite the vital role of optimal
artery diameter for brain function and the fact that PREG is a vasoactive agent, studies of
PREG on cerebral artery function are unavailable. My preliminary data support the idea that
PREG reduces both SM BK function and middle cerebral artery (MCA) diameter independently
of cytosolic/membrane receptors and downstream signaling. Rather, PREG actions seem to
result from direct sensing of PREG by specific BK subunits and targeting of distinct gating
mechanisms. Thus, I will study PREG actions on SM BK function and artery diameter using SM
cells, de-endothelialized, electroporated MCA, engineered BKs introduced into cells and tissues,
and will take advantage of BK subunit knockout mouse models. In a proposal that spans from
molecular to organ resolution, I will address two Aims: A1) Specific BK subunits and gating
mechanisms mediate PREG-induced inhibition of BK activity in MCA SM. Thus, I will establish
whether: 1.1) PREG inhibition of vascular SM BK is enabled by PREG direct sensing by specific
BK subunit(s) and a defined sensing site; 1.2) PREG sensitivity of BK is underlined by PREG
disruption of distinct gating mechanisms; 1.3) the direct action of PREG on BK remains in intact
SM cells. A2) PREG-induced MCA constriction results from steroid inhibition of SM BK. 2.1)
Comparison of key findings in male vs. female, natural vs. electroporated MCA will address the
roles of sex, BK subunits, and docking sites in PREG action. 2.2) I will confirm the ex-vivo data
in-vivo using a cranial window. I will be the first to address the molecular targets and gating
mechanisms mediating PREG action on brain vessels. Directed by Drs. Dopico and Bukiya at
UTHSC, the research will provide key concepts and methods (single channel electrophysiology,
Horrigan-Aldrich gating modeling, and rodent cranial window) to obtain my Ph.D. degree.

## Key facts

- **NIH application ID:** 10134765
- **Project number:** 1F31HL156290-01
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Kelsey Cleland North
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134765

## Citation

> US National Institutes of Health, RePORTER application 10134765, Pregnenolone constricts cerebral vascular arteries through the direct modulation of BK ion channels (1F31HL156290-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134765. Licensed CC0.

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