Ion Channel Regulation by the LKB1-AMPK Signalling Pathway: The Key to Carotid Body Activation by Hypoxia and Metabolic Homeostasis at the Whole Body Level

Abstract

Our recent investigations provide further support for the proposal that, consequent to inhibition of mitochondrial oxidative phosphorylation, activation of AMP-activated protein kinase (AMPK) mediates carotid body excitation by hypoxia. Consistent with the effects of hypoxia, intracellular dialysis from a patch pipette of an active (thiophosphorylated) recombinant AMPK heterotrimer (α2β2γ1) or application of the AMPK activators AICAR and A769662: (1) Inhibited BK(Ca) currents and TASK K(+) currents in rat carotid body type I cells; (2) Inhibited whole-cell currents carried by KCa1.1 and TASK3, but not TASK1 channels expressed in HEK293 cells; (3) Triggered carotid body activation. Furthermore, preliminary studies using mice with conditional knockout in type I cells of the primary upstream kinase that activates AMPK in response to metabolic stresses, LKB1, appear to confirm our working hypothesis. Studies on mice with knockout of the catalytic α1 subunit and α2 subunits of AMPK, respectively, have proved equally consistent. Accumulating evidence therefore suggests that the LKB1-AMPK signalling pathway is necessary for hypoxia-response coupling by the carotid body, and serves to regulate oxygen and therefore energy supply at the whole body level.

AMP-Activated Protein Kinase Directly Phosphorylates and Destabilizes Hedgehog Pathway Transcription Factor GLI1 in Medulloblastoma

“…AMPK has many target proteins that, together, allow coordinated shut down of energy-demanding activities (Hardie et al, 2012). Its activity can be triggered by stimuli such as exercise (Jessen et al, 2014) cytokines, and hypoxia (Evans et al, 2012). Targets have been identified in several ways, such as whole cell proteomics (Banko et al, 2011), in vitro tests (Gwinn et al, 2008), and genetics (Mihaylova and Shaw, 2011).…”

Sensing hypoxia: physiology, genetics and epigenetics

“…It is likely that the enzymes generating CO and H 2 S, in concert with K + channels in type I cells constitute important components of the 'chemosome' . Recent studies suggest that AMP kinase signalling also plays a role in hypoxic sensing by the carotid body (Evans et al 2012). It would be interesting to examine the potential cross-talk between the HO-2-CO and CSE-H 2 S systems with AMP kinase signalling in the carotid body in future studies.…”

Novel mutations in human and mouse SCN4A implicate AMPK in myotonia and periodic paralysis

“…Ion channels control muscle contractile activity and thus can affect ATP turnover in muscle fibres. AMPK activation has been reported to regulate ion channel activity directly (Evans et al , 2012) and indirectly (Light et al , 2003), thus providing a link between cellular energy demands and ion channel activity (Ingwersen et al , 2011; Andersen and Rasmussen, 2012). …”