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POPDC1 scaffolds a complex of adenylyl cyclase 9 and the potassium channel TREK-1 in heart

Tanya A Baldwin1, Yong Li1, Autumn N Marsden1

  • 1Department Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.

EMBO Reports
|October 18, 2022
PubMed

Insights

Popeye domain-containing (POPDC) proteins scaffold adenylyl cyclase 9 (AC9) and TREK-1 potassium channels, regulating heart rate. POPDC1 acts as an adaptor, influencing cardiac function and heart rate control.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cell Biology
  • Ion Channel Physiology

Background:

  • Scaffolding proteins are crucial for localized cAMP production by adenylyl cyclases (ACs), impacting cardiac functions.
  • Popeye domain-containing (POPDC) proteins are implicated in cardiac pacemaking and conduction through cAMP-dependent regulation of TREK-1 potassium channels.

Purpose of the Study:

  • To identify novel adenylyl cyclase (AC) scaffolds and elucidate their role in cardiac function.
  • To investigate the interaction between AC9, POPDC1, and TREK-1 potassium channels in the heart.

Main Methods:

  • Co-immunoprecipitation to assess protein complex formation.
  • Enzyme activity assays to measure adenylyl cyclase activity.
  • Gene deletion studies (Adcy9 knockout) to evaluate in vivo function.

Main Results:

  • POPDC1 identified as a novel scaffold for AC9, forming a complex with AC9 activity in the heart.
  • TREK-1 potassium channels bind to the AC9:POPDC1 complex in a POPDC1-dependent manner.
  • Beta-adrenergic receptor stimulation reduces TREK-1 association with the AC9:POPDC1 complex, requiring AC9 activity.

Conclusions:

  • POPDC1 acts as an adaptor protein, mediating interactions between AC9 and TREK-1 to regulate heart rate.
  • AC9 and POPDC1 are essential components in the signaling pathway controlling cardiac pacemaking and conduction.
  • Adcy9 deletion results in bradycardia and heart rate variability, phenotypically similar to TREK-1 loss.

Keywords:
ADCY9BVESTREK-1adenylyl cyclaseheart rate variability

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