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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
07:41

A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators

Published on: February 20, 2018

Interaction of alpha1-adrenoceptor subtypes with different G proteins induces opposite effects on cardiac L-type Ca2+

Jin O-Uchi1, Hiroyuki Sasaki, Satoshi Morimoto

  • 1Department of Cell Physiology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461 Japan. o-uchi@jikei.ac.jp

Circulation Research
|May 10, 2008
PubMed

Insights

Alpha-1A adrenoceptors enhance L-type Ca2+ current (ICa) via Gq/11 signaling, while Alpha-1B adrenoceptors inhibit ICa through Go proteins in rat heart cells.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Pharmacology
  • Cell Signaling

Background:

  • Alpha-1 adrenoceptors (α1-ARs) are crucial in regulating cardiac function.
  • Specific subtype roles in cardiac L-type Ca2+ current (ICa) modulation remain incompletely understood.
  • Understanding these mechanisms is key to targeting cardiovascular diseases.

Purpose of the Study:

  • To investigate the distinct effects of alpha-1A and alpha-1B adrenoceptor subtypes on rat ventricular myocyte ICa.
  • To elucidate the intracellular signaling pathways mediating these subtype-specific effects.
  • To determine the G protein coupling of each alpha-1 adrenoceptor subtype.

Main Methods:

  • Patch-clamp electrophysiology to measure ICa in isolated rat ventricular myocytes.
  • Selective adrenoceptor agonists and antagonists (A61603, WB4101) for subtype stimulation.
  • Pharmacological inhibitors (pertussis toxin, PLC, PKC, CaMKII inhibitors) to probe signaling pathways.
  • Western blotting and immunoprecipitation to confirm protein expression and G protein interactions.

Main Results:

  • Selective alpha-1A stimulation potentiated ICa, dependent on Gq/11-PLC-PKC-CaMKII signaling.
  • Selective alpha-1B stimulation inhibited ICa, mediated by pertussis toxin-sensitive G proteins (likely Go).
  • Alpha-1A stimulation led to PKCδ/ε translocation to T-tubules; alpha-1B stimulation did not.

Conclusions:

  • Alpha-1A and alpha-1B adrenoceptors exert opposing effects on cardiac ICa through distinct G protein-coupled pathways.
  • Alpha-1A activation potentiates ICa via Gq/11-mediated cascades.
  • Alpha-1B activation inhibits ICa, potentially via direct Gi/o betagamma subunit interaction with the channel.

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