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The LRRC26 protein selectively alters the efficacy of BK channel activators

Janos Almassy1, Ted Begenisich

  • 1Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.

Molecular Pharmacology
|October 11, 2011
PubMed

Insights

Mallotoxin (MTX) activates large conductance calcium-activated potassium (BK) channels, but its effect is reduced by the accessory protein LRRC26 in native parotid cells. LRRC26 selectively alters BK channel pharmacology.

Area of Science:

  • Biophysics
  • Molecular Biology
  • Pharmacology

Background:

  • Large conductance, calcium-activated potassium (BK) channels are crucial for numerous physiological processes.
  • Mallotoxin (MTX) is a known potent activator of BK channels, significantly altering their voltage gating and activity.
  • Understanding BK channel pharmacology is vital due to their diverse physiological roles.

Purpose of the Study:

  • To investigate the differential effects of mallotoxin (MTX) on BK channels in native parotid acinar cells versus heterologously expressed channels.
  • To determine the role of the accessory protein LRRC26 in modulating the response of parotid BK channels to MTX and other activators.
  • To elucidate the selective pharmacological impact of LRRC26 on BK channel activation.

Main Methods:

  • Electrophysiological recordings (e.g., patch-clamp) to measure BK channel activity and gating kinetics.
  • Heterologous expression of BK channel isoforms (parSlo) with and without the LRRC26 accessory protein.
  • Application of pharmacological agents, including MTX and NS-1619, to assess their effects on channel function.

Main Results:

  • MTX caused a minimal shift in steady-state activation of BK channels in native parotid acinar cells (6 mV), contrasting with large shifts in heterologously expressed channels (70 mV).
  • Despite minimal steady-state effects, MTX approximately doubled the gating kinetics of BK channels in parotid cells.
  • The accessory protein LRRC26, expressed in parotid glands, rendered parSlo BK channels resistant to MTX activation but had minimal impact on NS-1619 efficacy.
  • Parotid BK channels exhibit a more hyperpolarized voltage activation range, potentially due to LRRC26.

Conclusions:

  • The accessory protein LRRC26 selectively alters the pharmacology of large conductance calcium-activated potassium channels.
  • LRRC26 confers resistance to MTX activation while largely preserving sensitivity to benzimidazolone activators like NS-1619.
  • These findings highlight the crucial role of accessory proteins in fine-tuning BK channel function and drug response in native tissues.

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