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

doi:10.1038/s42003-022-03583-7

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 journal › Article › peer-review

8 Downloads (Pure)

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 language	English
Article number	642
Number of pages	15
Journal	Communications Biology
Volume	5
Issue number	1
Early online date	29 Jun 2022
DOIs	https://doi.org/10.1038/s42003-022-03583-7
Publication status	Published - Dec 2022

Bibliographical note

© 2022. The Author(s).

Funding Information:
This work was primarily funded by a Wellcome Trust Programme Grant held by AME (WT081195MA), which also supported by subcontract the work of A.P.H and P.K. at the University of Birmingham. S.M. was supported by a University of Edinburgh Ph.D. studentship and then by a BHF Programme Grant held by AME (RG/12/14/29885). We thank Matthew Bailey for his kind support of blood gas measurements.

Publisher Copyright:
© 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

ASJC Scopus subject areas

Agricultural and Biological Sciences(all)
Biochemistry, Genetics and Molecular Biology(all)
Medicine (miscellaneous)

Access to Document

10.1038/s42003-022-03583-7Licence: Creative Commons: Attribution (CC BY)

MacMillanS2022LKB1Final published version, 2.44 MBLicence: Creative Commons: Attribution (CC BY)

Cite this

@article{6d3e296f6964422ba67df36418a4642f,

title = "LKB1 is the gatekeeper of carotid body chemosensing and the hypoxic ventilatory response",

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.",

keywords = "AMP-Activated Protein Kinase Kinases/metabolism, AMP-Activated Protein Kinases/metabolism, Apnea, Carotid Body/metabolism, Humans, Hypercapnia/metabolism, Hypoventilation/metabolism, Hypoxia/metabolism",

author = "Sandy MacMillan and Holmes, {Andrew P} and Dallas, {Mark L} and Mahmoud, {Amira D} and Shipston, {Michael J} and Chris Peers and Hardie, {D Grahame} and Prem Kumar and Evans, {A Mark}",

note = "{\textcopyright} 2022. The Author(s). Funding Information: This work was primarily funded by a Wellcome Trust Programme Grant held by AME (WT081195MA), which also supported by subcontract the work of A.P.H and P.K. at the University of Birmingham. S.M. was supported by a University of Edinburgh Ph.D. studentship and then by a BHF Programme Grant held by AME (RG/12/14/29885). We thank Matthew Bailey for his kind support of blood gas measurements. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s42003-022-03583-7",

language = "English",

volume = "5",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - LKB1 is the gatekeeper of carotid body chemosensing and the hypoxic ventilatory response

AU - MacMillan, Sandy

AU - Holmes, Andrew P

AU - Dallas, Mark L

AU - Mahmoud, Amira D

AU - Shipston, Michael J

AU - Peers, Chris

AU - Hardie, D Grahame

AU - Kumar, Prem

AU - Evans, A Mark

N1 - © 2022. The Author(s). Funding Information: This work was primarily funded by a Wellcome Trust Programme Grant held by AME (WT081195MA), which also supported by subcontract the work of A.P.H and P.K. at the University of Birmingham. S.M. was supported by a University of Edinburgh Ph.D. studentship and then by a BHF Programme Grant held by AME (RG/12/14/29885). We thank Matthew Bailey for his kind support of blood gas measurements. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

KW - AMP-Activated Protein Kinase Kinases/metabolism

KW - AMP-Activated Protein Kinases/metabolism

KW - Apnea

KW - Carotid Body/metabolism

KW - Humans

KW - Hypercapnia/metabolism

KW - Hypoventilation/metabolism

KW - Hypoxia/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85133131051&partnerID=8YFLogxK

U2 - 10.1038/s42003-022-03583-7

DO - 10.1038/s42003-022-03583-7

M3 - Article

C2 - 35768580

SN - 2399-3642

VL - 5

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 642

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

Fingerprint

Cite this