title: AMP kinase regulates K-ATP currents evoked by NMDA receptor stimulation in rat subthalamic nucleus neurons.
abstract: Our lab recently showed that N-methyl-D-aspartate (NMDA) evokes ATP-sensitive K(+) (K-ATP) currents in subthalamic nucleus (STN) neurons in slices of the rat brain. Both K-ATP channels and 5'-adenosine monophosphate-activated protein kinase (AMPK) are considered cellular energy sensors because their activities are influenced by the phosphorylation state of adenosine nucleotides. Moreover, AMPK has been shown to regulate K-ATP function in a variety of tissues including pancreas, cardiac myocytes, and hypothalamus. We used whole-cell patch clamp recordings to study the effect of AMPK activation on K-ATP channel function in STN neurons in slices of the rat brain. We found that bath or intracellular application of the AMPK activators A769662 and PT1 augmented tolbutamide-sensitive K-ATP currents evoked by NMDA receptor stimulation. The effect of AMPK activators was blocked by the AMPK inhibitor dorsomorphin (compound C), and by STO609, an inhibitor of the upstream AMPK activator CaMKKβ. AMPK augmentation of NMDA-induced K-ATP current was also blocked by intracellular BAPTA and by inhibitors of nitric oxide synthase and guanylyl cyclase. However, A769662 did not augment currents evoked by the K-ATP channel opener diazoxide. In the presence of NMDA, A769662 inhibited depolarizing plateau potentials and burst firing, both of which could be antagonized by tolbutamide or dorsomorphin. These studies show that AMPK augments NMDA-induced K-ATP currents by a Ca(2+)-dependent process that involves nitric oxide and cGMP. By augmenting K-ATP currents, AMPK activation would be expected to dampen the excitatory effect of glutamate-mediated transmission in the STN.
authors.affiliation: Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: K-Z
authors.initials: KZ
authors.lastname: Shen
authors.affiliation: Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: V
authors.initials: V
authors.lastname: Yakhnitsa
authors.affiliation: Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Munhall
authors.affiliation: Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA; Portland Veterans Affairs Medical Center, Portland, OR 97207, USA. Electronic address: johnsost@ohsu.edu.
authors.forename: S W
authors.initials: SW
authors.lastname: Johnson
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D020530:Subthalamus / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*
chemical_list: D018690:Excitatory Amino Acid Agonists; D054086:KATP Channels; D011720:Pyrazoles; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; C516138:dorsomorphin; D016202:N-Methylaspartate; D055372:AMP-Activated Protein Kinases
keywords: AMP kinase; Brain slice; K-ATP; NMDA; Patch-clamp; Subthalamic nucleus