# Ion Channels and Membrane Receptors in Pulmonary Arterial Hypertension

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $789,719

## Abstract

Project Summary/Abstract
Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease. Sustained pulmonary
vasoconstriction and vascular remodeling are the major causes for the elevated PVR and PAP in IPAH
patients. An increase in cytosolic Ca ([Ca ]cyt) in pulmonary arterial smooth muscle cells (PASMC) is a major
 2+ 2+
trigger for pulmonary vasoconstriction and for pulmonary vascular remodeling due to its stimulatory effect on
PASMC proliferation and migration. Abnormally enhanced Ca2+ entry in PASMC because of upregulated
expression of membrane receptors (e.g., CaSR) and Ca2+ channels (e.g., TRPC6/C3) contributes to the
development and progression of PAH. Downregulation of voltage-gated K+ (Kv) channel expression and
decrease in Kv currents (IK(V)) in PASMC contribute to a) increasing PASMC contraction, proliferation and
migration by inducing membrane depolarization that opens voltage-dependent Ca2+ channels and raises
[Ca ]cyt and b) inhibiting PASMC apoptosis by attenuating apoptotic volume decrease (AVD) and maintaining
2+
high [K ]cyt to inhibit caspases. Enhanced PASMC proliferation and inhibited PASMC apoptosis both contribute
 +
to pulmonary vascular wall thickening. Our data show that selectively increased miRNAs are involved in
posttranscriptionally downregulating Kv channels to stimulate PASMC proliferation and inhibit PASMC
apoptosis in IPAH patients. Ca2+-sensing receptor (CaSR), a G protein-coupled receptor that can be activated
by extracellular Ca2+, is upregulated in IPAH-PASMC compared to normal PASMC. Activation of CaSR in
IPAH-PASMC induces receptor-operated Ca entry (ROCE) via diacylglycerol (DAG), while IP3-mediate active
2+
depletion of Ca2+ from the SR results in store-operated Ca2+ entry (SOCE). Extracellular Ca2+-induced CaSR
activation also inhibits Kv channels and activate other signal transduction pathways to induce cell proliferation.
The overall goal of this research program is to continue to investigate: i) the molecular and cellular
mechanisms involved in the posttranscriptional downregulation of Kv channels and other K+ channels by
miRNAs that are enhanced in PASMC from IPAH patients; ii) the genetic and molecular mechanisms
responsible for the transcriptional upregulation of CaSR and receptor-operated (ROC) and store-operated
(SOC) Ca2+ channels (e.g., TRPC3/C6, TRPV1, Orai1/2 and STIM1/2) in PASMC from IPAH patients; iii) the
cellular and pathophysiological mechanisms involved in the CaSR-mediated functional activation of TRPC/Orai
channels (and STIM1/2 oligomerization and translocation) and functional inhibition of Kv channels in PASMC
from IPAH patients; and iv) the potential targets involved in the pathogenic Ca2+ signaling that can be used to
develop novel therapy or combination therapy for PAH. Our laboratory has extensive research and technical
experience in studying pathogenic mechanisms of IPAH and pulmonary hypertension associated with hypoxic
lung disease. The forthcoming resu...

## Key facts

- **NIH application ID:** 10563148
- **Project number:** 5R35HL135807-08
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jason X J Yuan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $789,719
- **Award type:** 5
- **Project period:** 2017-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10563148

## Citation

> US National Institutes of Health, RePORTER application 10563148, Ion Channels and Membrane Receptors in Pulmonary Arterial Hypertension (5R35HL135807-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10563148. Licensed CC0.

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