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Many cellular signals are hydrophilic and therefore cannot pass through the plasma membrane. However, small or hydrophobic signaling molecules can cross the hydrophobic core of the plasma membrane and bind to internal, or intracellular, receptors that reside within the cell. Many mammalian steroid hormones use this mechanism of cell signaling, as does nitric oxide (NO) gas.
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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
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Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
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Pharmacological regulation of airway ciliary motility: endogenous mediators, pharmaceutical agents, and natural compounds with a focus on ginsenoside Rd.

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Updated: May 23, 2025

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Ginsenoside Rd Activates Ciliary Beat Frequency via Estrogen Receptor β and P2X7 Receptor.

Kouta Noriyama1, Shigekuni Hosogi1, Seikou Nakamura2

  • 1Laboratory of Clinical and Translational Physiology, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.

Biological & Pharmaceutical Bulletin
|May 21, 2025
PubMed
Summary

Ginsenoside Rd effectively increases ciliary beat frequency (CBF), a key measure of airway clearance. It acts by activating estrogen receptor beta (ERβ) and modulating the P2X7 receptor.

Keywords:
airway ciliated cellciliary beat frequencyestrogen receptor βginsenoside Rdpurinergic 2X7 receptor

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Area of Science:

  • Respiratory physiology
  • Pharmacology
  • Cell biology

Background:

  • The human airway epithelium, comprising basal, goblet, and ciliated cells, is crucial for mucociliary clearance (MCC).
  • Ciliary beat frequency (CBF) is a critical indicator of MCC efficiency, but the specific compounds responsible for enhancing CBF in herbal medicines remain largely unidentified.
  • Understanding these compounds and their mechanisms is vital for developing therapies to improve airway clearance.

Purpose of the Study:

  • To identify specific compounds that directly increase CBF and elucidate their underlying mechanisms of action.
  • To investigate the role of ginsenosides and their derivatives in modulating airway epithelial function.
  • To determine the molecular targets responsible for ginsenoside Rd's effects on CBF.

Main Methods:

  • Screening of ginsenosides and derivatives for their ability to increase CBF and intracellular cAMP concentration ([cAMP]i).
  • Identification of molecular targets, including estrogen receptor beta (ERβ) and the P2X7 receptor.
  • Assessment of ginsenoside Rd's effects on intracellular calcium ([Ca2+]i) and potentiation of ATP-induced CBF increases in murine airway ciliated cells.

Main Results:

  • Ginsenoside Rd demonstrated the most significant increase in CBF and intracellular cAMP concentration ([cAMP]i among screened compounds.
  • Estrogen receptor beta (ERβ) was identified as a novel target for ginsenoside Rd-mediated increases in [cAMP]i and CBF.
  • Ginsenoside Rd increased intracellular calcium ([Ca2+]i) and acted as a positive allosteric modulator (PAM) of the P2X7 receptor, enhancing ATP-induced CBF.

Conclusions:

  • Ginsenoside Rd effectively increases CBF through dual mechanisms.
  • Its action involves agonism of estrogen receptor beta (ERβ) and positive allosteric modulation of the P2X7 receptor.
  • These findings provide a mechanistic basis for the use of ginsenoside Rd in conditions affecting airway clearance.