LKB1 is the gatekeeper of carotid body chemosensing and the hypoxic ventilatory response

Sandy MacMillan, Andrew P Holmes, Mark L Dallas, Amira D Mahmoud, Michael J Shipston, Chris Peers, D Grahame Hardie, Prem Kumar, A Mark Evans

Research output: Contribution to journalArticlepeer-review

Abstract

The hypoxic ventilatory response (HVR) is critical to breathing and thus oxygen supply to the body and is primarily mediated by the carotid bodies. Here we reveal that carotid body afferent discharge during hypoxia and hypercapnia is determined by the expression of Liver Kinase B1 (LKB1), the principal kinase that activates the AMP-activated protein kinase (AMPK) during metabolic stresses. Conversely, conditional deletion in catecholaminergic cells of AMPK had no effect on carotid body responses to hypoxia or hypercapnia. By contrast, the HVR was attenuated by LKB1 and AMPK deletion. However, in LKB1 knockouts hypoxia evoked hypoventilation, apnoea and Cheyne-Stokes-like breathing, while only hypoventilation and apnoea were observed after AMPK deletion. We therefore identify LKB1 as an essential regulator of carotid body chemosensing and uncover a divergence in dependency on LKB1 and AMPK between the carotid body on one hand and the HVR on the other.

Original languageEnglish
Article number642
Number of pages15
JournalCommunications Biology
Volume5
Issue number1
Early online date29 Jun 2022
DOIs
Publication statusE-pub ahead of print - 29 Jun 2022

Bibliographical note

© 2022. The Author(s).

Keywords

  • AMP-Activated Protein Kinase Kinases/metabolism
  • AMP-Activated Protein Kinases/metabolism
  • Apnea
  • Carotid Body/metabolism
  • Humans
  • Hypercapnia/metabolism
  • Hypoventilation/metabolism
  • Hypoxia/metabolism

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