Related Experiment Video

Updated: Dec 4, 2025

Imaging Ca2+ Signals in Small Pulmonary Veins at Physiological Intraluminal Pressures
05:35

Imaging Ca2+ Signals in Small Pulmonary Veins at Physiological Intraluminal Pressures

Published on: March 21, 2025

531

PKCζ-NADPH Oxidase-PKCα Dependent Kv1.5 Phosphorylation by Endothelin-1 Modulates Nav1.5-NCX1-Cav1.2 Axis in

Jaganmay Sarkar1, Tapati Chakraborti1, Pijush Kanti Pramanik1

  • 1Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, 741235, India.

Cell Biochemistry and Biophysics
|October 23, 2020
PubMed

Insights

Endothelin-1 (ET-1) increases pulmonary hypertension by raising intracellular calcium in pulmonary artery cells. This study reveals ET-1 activates a signaling pathway involving PKC-alpha and Kv1.5 channels, modulating ion channels to increase calcium in caveolae vesicles.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cell Biology
  • Pulmonary Hypertension Research

Background:

  • Endothelin-1 (ET-1) is a potent vasoconstrictor that elevates pulmonary artery pressure.
  • ET-1 increases intracellular calcium ([Ca2+]i) in pulmonary artery smooth muscle cells (PASMCs), contributing to pulmonary hypertension.
  • The precise mechanisms of ET-1-induced calcium signaling within caveolae vesicles of PASMCs remain incompletely understood.

Purpose of the Study:

  • To elucidate the signaling pathway by which ET-1 stimulates calcium concentration in caveolae vesicles of bovine PASMCs (BPASMCs).
  • To investigate the roles of specific ion channels and signaling molecules, including PKC-alpha, Kv1.5, Cav1.2, Nav1.5, and NCX-1, in ET-1-mediated calcium regulation.
  • To explore the effects of Kv channel inhibition on calcium concentration in BPASMC caveolae vesicles.

Main Methods:

  • Investigated ET-1-induced activation of PKC-alpha within caveolae vesicles via a PKCζ-NADPH oxidase-dependent pathway.
  • Examined the phosphorylation of Kv1.5 channels by PKC-alpha and its impact on Na+ and Ca2+ concentrations.
  • Analyzed the contribution of Cav1.2, Nav1.5, and NCX-1 channels to ET-1-mediated calcium influx and regulation.
  • Assessed the effects of 4-aminopyridine (4-AP), a Kv channel inhibitor, on calcium dynamics independent of the PKC pathway.

Main Results:

  • ET-1 activates PKC-alpha in caveolae vesicles, leading to Kv1.5 channel phosphorylation and increased Na+ and Ca2+ concentrations.
  • ET-1-induced calcium increase in caveolae vesicles is primarily mediated by Cav1.2 channels.
  • ET-1 also increases Ca2+ via Nav1.5 channels, reverse-mode NCX-1, and Nav1.5 slip-mode conductance.
  • 4-AP increases caveolae Ca2+ via Cav1.2, reverse-mode NCX-1, and Nav1.5 channels, independent of the PKCζ-NADPH oxidase-PKCα axis.

Conclusions:

  • ET-1 stimulates calcium concentration in BPASMC caveolae vesicles through a PKCζ-NADPH oxidase-PKCα-dependent phosphorylation of Kv1.5 channels.
  • This pathway modulates the Nav1.5-NCX1-Cav1.2 axis, impacting pulmonary vascular tone.
  • Understanding this mechanism provides critical insights into ET-1's role in pulmonary hypertension.
Keywords:
CalciumEndothelin-1NADPH oxidasePulmonary artery smooth muscle cells, caveolae vesiclesVoltage gated ion channels, protein kinase C

More Related Videos

Isolation of Intrapulmonary Artery and Smooth Muscle Cells to Investigate Vascular Responses07:56

Isolation of Intrapulmonary Artery and Smooth Muscle Cells to Investigate Vascular Responses

Published on: June 8, 2022

4.6K
Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium08:46

Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium

Published on: September 1, 2015

10.1K

Related Concept Videos

Nitric Oxide Signaling Pathway01:28

Nitric Oxide Signaling Pathway

Nitric oxide (NO), an inorganic gas, acts as a potent second messenger in most animal and plant tissues. NO diffuses out of the cells that produce it and enters the neighboring cells to generate a downstream response. NO synthase (NOS) catalyzes NO production by the deamination of the amino acid arginine. There are three isoforms of NOS. Endothelial cells have endothelial NOS (eNOS), nerve and muscle cells have neuronal NOS (nNOS), and macrophages produce inducible NOS (iNOS) upon exposure...
5.9K
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
3.1K
Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers01:26

Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers

Receptor tyrosine kinase inhibitors (TKIs) and calcium channel blockers (CCBs) are two critical categories of drugs employed in the treatment of pulmonary artery hypertension (PAH). PAH is a disease that causes high blood pressure in the pulmonary arteries, resulting in chest pain, fatigue, and shortness of breath.
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
344
Antihypertensive Drugs: Vasodilators01:23

Antihypertensive Drugs: Vasodilators

Vasodilators, primarily affecting the smooth muscles within arterial and venous walls, are commonly used for hypertension treatment. Medications such as minoxidil and hydralazine primarily target arteries and arterioles, while sodium nitroprusside acts on arterioles and venules. Minoxidil, functioning as a prodrug, is metabolized by hepatic sulfotransferase into its active form, minoxidil sulfate, after oral administration. This metabolite binds to the sulfonylurea receptor (SUR) component of...
1.8K
Antihypertensive Drugs: Action of Calcium Channel Blockers01:18

Antihypertensive Drugs: Action of Calcium Channel Blockers

Calcium ions are essential to contract smooth muscle cells in blood vessels. They enter these cells through voltage-dependent calcium channels, specifically L-type calcium channels in the cell membrane. These L-type calcium channels are integral to the excitation-contraction coupling process in smooth muscle. When a stimulus is received by smooth muscle cells, their membrane depolarizes. This alteration in membrane potential instigates the opening of L-type calcium channels. As a result,...
1.3K
Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
5.7K