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Activation of a PTX-insensitive G protein is involved in histamine-induced recombinant M-channel modulation

Juan Guo1, Geoffery G Schofield

  • 1Department of Physiology, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.

The Journal of Physiology
|December 17, 2002
PubMed

Insights

Histamine inhibits M-type potassium current (I(M)) by modulating KCNQ2/3 channels. This process involves a pertussis toxin-insensitive G protein, likely Gαq/11, and novelly implicates βγ subunits.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • M-type potassium current (I(M)) is crucial for regulating neuronal excitability.
  • Signal transduction pathways for M-channel modulation by neurotransmitters are not fully understood, except for bradykinin.
  • KCNQ2 and KCNQ3 subunits coassemble to form channels underlying I(M), which can be modulated by histamine H1 receptors.

Purpose of the Study:

  • To elucidate the signal transduction pathways involved in histamine-induced modulation of M-type potassium channels.
  • To investigate the role of G proteins, specifically Gαq/11 and βγ subunits, in this modulation.
  • To characterize the effects of histamine on the biophysical properties of recombinant M-channels.

Main Methods:

  • Heterologous expression of KCNQ2/3 channels in HEK293T cells.
  • Electrophysiological recordings to measure M-type potassium current (I(M)).
  • Pharmacological treatments including pertussis toxin (PTX) and guanine nucleotide analogues (GDP-β-S, GTP-γ-S).
  • Expression of specific constructs to interfere with G protein signaling pathways (e.g., PLC-β1-ct, Galphat, MAS-GRK2-ct).

Main Results:

  • Histamine, acting via H1 receptors, strongly inhibited recombinant M-channels without altering voltage dependence.
  • Histamine accelerated M-channel gating, particularly deactivation, in a voltage-insensitive manner.
  • PTX-insensitive G protein involvement was confirmed by nucleotide analogues and PTX treatment.
  • Gαq/11 subunits were implicated via PLC-β1-ct, while βγ subunits were implicated via Galphat and MAS-GRK2-ct.

Conclusions:

  • Histamine modulates KCNQ2/3 M-channels through a PTX-insensitive G protein pathway, likely involving Gαq/11.
  • This modulation is novel in its apparent involvement of both Gαq/11 and βγ subunits.
  • The findings provide new insights into the complex signaling mechanisms regulating neuronal excitability via M-channels.

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