LKB1 is the gatekeeper of carotid body chemo-sensing and the hypoxic ventilatory response: deficiency precipitates Cheyne Stokes breathing

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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 mediates AMPK activation during metabolic stresses. Conversely, conditional deletion in catecholaminergic cells of AMPK, the principal downstream target of LKB1, 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 a novel and essential regulator of carotid body chemo-sensing and uncover a divergence in dependency on LKB1 and AMPK between the carotid body on one hand and the HVR on the other.