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LKB1 is the gatekeeper of carotid body chemo-sensing and the hypoxic ventilatory response

MacMillan, S.; Holmes, A. P.; Dallas, M. L.; Mahmoud, A. D.; Shipston, M. J.; Hardie, D. G.; Kumar, P.; Evans, A. M.

2022-05-24 physiology
10.1101/2022.05.24.493275 bioRxiv
Show 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.

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