Vascular KATP Channel Modulation in Hypercapnic Acidosis

Summary

Principal Investigator: C Jiang
Abstract: ATP-sensitive K+ channels (KATP) couple the intermediary metabolism to cellular excitability, and play an important role in reactive hyperemia. It is known that hyperemia underlies the cardio-protective effect of ischemic preconditioning and the activity-dependent auto-regulation of cerebral circulation, and involves sensing of O2, CO2 and pH. Our recent studies indicate that KATP channels are indeed activated with high COz / low pH. The regulation of KATP by protons is significant, because a drop in pH levels often accompanies various metabolic stresses and is more frequently seen than sole energy depletion. Such regulation may enable cells to change their membrane excitability in response to a wide variety of physiologic and pathophysiologic conditions. However, previous studies on the pH sensitivity were rather controversial: proton was shown to stimulate cell-endogenous KATP in some studies but inhibit it in others. The inconsistence is further complicated by the indirect effect of ATP, ADP and Mg ++ on channel activity. Thereby, it is unclear how the KATP is modulated during hypercapnia and acidosis, whether these channels are inherently pH-sensitive, and what the molecular mechanisms underlying the modulation are. The cloned KATP channels are ideal for addressing these questions, which allow a fine dissection of the modulatory mechanisms and elaborate manipulations of PCO2 and pH in the expression system. Thereby, we have been studying the pH sensitivity of the cloned KATP over the past 3 years. Our preliminary data have clearly shown that proton is a potent activator of the KATP. TO further these observations, we have proposed studies aimed at 1) elucidating the modulation of KATP by hypercapnia and acidosis, 2) demonstrating the sensing mechanisms in the channel proteins, 3) determining factors and their interactions with protons in regulating the pH sensitivity, and 4) identifying the pH-sensitive KATP isoforms in vascular smooth muscles. This information should have profound impacts not only on cardiovascular physiology but also on the design of therapeutical modalities by manipulating the pH-sensing mechanisms to control cellular activity in stroke, epilepsy and coronary heart disease.
Funding Period: 2003-07-01 - 2008-06-30
more information: NIH RePORT

Top Publications

  1. pmc Differential sensitivities of the vascular K(ATP) channel to various PPAR activators
    Yingji Wang
    Department of Biology, Georgia State University, Atlanta, GA 30302 4010, USA
    Biochem Pharmacol 85:1495-503. 2013
  2. pmc Rosiglitazone inhibits vascular KATP channels and coronary vasodilation produced by isoprenaline
    Lei Yu
    Department of Biology, Georgia State University, Atlanta, GA 30302, USA
    Br J Pharmacol 164:2064-72. 2011
  3. pmc Lipopolysaccharides up-regulate Kir6.1/SUR2B channel expression and enhance vascular KATP channel activity via NF-kappaB-dependent signaling
    Weiwei Shi
    Department of Biology, Georgia State University, Atlanta, Georgia 30303, USA
    J Biol Chem 285:3021-9. 2010
  4. pmc K(ATP) channel action in vascular tone regulation: from genetics to diseases
    Wei Wei Shi
    Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, Emory University, Atlanta, GA 30308, USA
    Sheng Li Xue Bao 64:1-13. 2012
  5. pmc Protein kinase C dependent inhibition of the heteromeric Kir4.1-Kir5.1 channel
    Asheebo Rojas
    Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30302 4010, USA
    Biochim Biophys Acta 1768:2030-42. 2007
  6. pmc PKA phosphorylation of SUR2B subunit underscores vascular KATP channel activation by beta-adrenergic receptors
    Yun Shi
    Department of Biology, Georgia State University, 24 Peachtree Center Ave, Atlanta, GA 30302, USA
    Am J Physiol Regul Integr Comp Physiol 293:R1205-14. 2007
  7. pmc PKA-dependent activation of the vascular smooth muscle isoform of KATP channels by vasoactive intestinal polypeptide and its effect on relaxation of the mesenteric resistance artery
    Yang Yang
    Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, Georgia 30302 4010, USA
    Biochim Biophys Acta 1778:88-96. 2008
  8. pmc Hypercapnia modulates synaptic interaction of cultured brainstem neurons
    Liang Yang
    Department of Biology, Georgia State University, 33 Gilmer Street, Atlanta, GA 30303, USA
    Respir Physiol Neurobiol 160:147-59. 2008
  9. pmc A short motif in Kir6.1 consisting of four phosphorylation repeats underlies the vascular KATP channel inhibition by protein kinase C
    Yun Shi
    Department of Biology, Georgia State University, 33 Gilmer Street, Atlanta, GA 30302 4010, USA
    J Biol Chem 283:2488-94. 2008
  10. pmc cAMP-dependent protein kinase phosphorylation produces interdomain movement in SUR2B leading to activation of the vascular KATP channel
    Yun Shi
    Department of Biology, Georgia State University, Atlanta, Georgia 30302 4010, USA
    J Biol Chem 283:7523-30. 2008

Scientific Experts

  • C Jiang
  • Ningren Cui
  • Yun Shi
  • Weiwei Shi
  • Junda Su
  • Yang Yang
  • Asheebo Rojas
  • Xiaoli Zhang
  • Runping Wang
  • Liang Yang
  • Lei Yu
  • Xueren Wang
  • Daling Zhu
  • Zhongying Wu
  • Yingji Wang
  • Li Li
  • Xin Jin
  • Wei Wei Shi
  • Shuang Zhang
  • Jianping Wu
  • Hailan Piao
  • R Wang
  • Hongyu Gai
  • Ming Lee
  • Shouli Guo
  • Xianfeng Chen
  • Dyanna Fountain
  • Robert W Harrison
  • Jean Pierre Muhumuza
  • Binh T Ha
  • Vivian A Onyebuchi
  • C Y Adams
  • H Piao
  • Carmen Y Adams
  • H Xu
  • Y Wang
  • J Wu
  • Y Shi
  • A Rojas

Detail Information

Publications22

  1. pmc Differential sensitivities of the vascular K(ATP) channel to various PPAR activators
    Yingji Wang
    Department of Biology, Georgia State University, Atlanta, GA 30302 4010, USA
    Biochem Pharmacol 85:1495-503. 2013
    ..The structural information of the PPAR agonists may be useful for the development of new therapeutical modalities with less cardiovascular side-effects...
  2. pmc Rosiglitazone inhibits vascular KATP channels and coronary vasodilation produced by isoprenaline
    Lei Yu
    Department of Biology, Georgia State University, Atlanta, GA 30302, USA
    Br J Pharmacol 164:2064-72. 2011
    ..Here, we show that the vascular isoform of the ATP-sensitive K(+) (K(ATP) ) channel is inhibited by rosiglitazone, impairing physiological regulation of the coronary circulation...
  3. pmc Lipopolysaccharides up-regulate Kir6.1/SUR2B channel expression and enhance vascular KATP channel activity via NF-kappaB-dependent signaling
    Weiwei Shi
    Department of Biology, Georgia State University, Atlanta, Georgia 30303, USA
    J Biol Chem 285:3021-9. 2010
    ..1 and SUR2B expression to a similar degree as LPS. Thus, the effect of LPS on vasodilation involves up-regulation of K(ATP) channel expression, in which the NF-kappaB-dependent signaling plays an important role...
  4. pmc K(ATP) channel action in vascular tone regulation: from genetics to diseases
    Wei Wei Shi
    Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, Emory University, Atlanta, GA 30308, USA
    Sheng Li Xue Bao 64:1-13. 2012
    ....
  5. pmc Protein kinase C dependent inhibition of the heteromeric Kir4.1-Kir5.1 channel
    Asheebo Rojas
    Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30302 4010, USA
    Biochim Biophys Acta 1768:2030-42. 2007
    ..Taken together, these results suggest that the Kir4.1-Kir5.1 but not the homomeric Kir4.1 channel is strongly inhibited by PKC activation...
  6. pmc PKA phosphorylation of SUR2B subunit underscores vascular KATP channel activation by beta-adrenergic receptors
    Yun Shi
    Department of Biology, Georgia State University, 24 Peachtree Center Ave, Atlanta, GA 30302, USA
    Am J Physiol Regul Integr Comp Physiol 293:R1205-14. 2007
    ..Taken together, these results indicate that the Kir6.1/SUR2B channel is a target of beta(2) receptors and that the channel activation relies on PKA phosphorylation of SUR2B at Ser1387...
  7. pmc PKA-dependent activation of the vascular smooth muscle isoform of KATP channels by vasoactive intestinal polypeptide and its effect on relaxation of the mesenteric resistance artery
    Yang Yang
    Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, Georgia 30302 4010, USA
    Biochim Biophys Acta 1778:88-96. 2008
    ..These results therefore indicate that the vascular isoform (Kir6.1/SUR2B) of KATP channels is a target of VIP. The channel activation relies on the PKA pathway and produces mesenteric arterial relaxation...
  8. pmc Hypercapnia modulates synaptic interaction of cultured brainstem neurons
    Liang Yang
    Department of Biology, Georgia State University, 33 Gilmer Street, Atlanta, GA 30303, USA
    Respir Physiol Neurobiol 160:147-59. 2008
    ..Based on these indirect assessments of synaptic interaction, our PEH analysis suggests that hypercapnia appears to modulate excitatory synaptic transmissions, especially those between CO(2)-stimulated neurons...
  9. pmc A short motif in Kir6.1 consisting of four phosphorylation repeats underlies the vascular KATP channel inhibition by protein kinase C
    Yun Shi
    Department of Biology, Georgia State University, 33 Gilmer Street, Atlanta, GA 30302 4010, USA
    J Biol Chem 283:2488-94. 2008
    ..1, but not in its close relative Kir6.2, suggests that the vascular K(ATP) channel may have undergone evolutionary optimization, allowing it to be regulated by a variety of vasoconstricting hormones and neurotransmitters...
  10. pmc cAMP-dependent protein kinase phosphorylation produces interdomain movement in SUR2B leading to activation of the vascular KATP channel
    Yun Shi
    Department of Biology, Georgia State University, Atlanta, Georgia 30302 4010, USA
    J Biol Chem 283:7523-30. 2008
    ..Thus, a channel-gating mechanism is suggested through enhancing the NBD-TMD coupling efficiency following Ser-1387 phosphorylation, which is shared by multiple vasodilators...
  11. pmc Modulation of the heteromeric Kir4.1-Kir5.1 channel by multiple neurotransmitters via Galphaq-coupled receptors
    Asheebo Rojas
    Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, Georgia 30302 4010, USA
    J Cell Physiol 214:84-95. 2008
    ..1-Kir5.1 channel is modulated by the neurotransmitters critical for respiratory control, suggesting a novel neuromodulatory mechanism for the chemosensitivity of brainstem neurons to elevated PCO(2) and acidic pH...
  12. ncbi Kir6.2 channel gating by intracellular protons: subunit stoichiometry for ligand binding and channel gating
    Runping Wang
    Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, Georgia, 30303 4010, USA
    J Membr Biol 213:155-64. 2006
    ....
  13. ncbi CO2 central chemosensitivity: why are there so many sensing molecules?
    Chun Jiang
    Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta GA 30302 4010, USA
    Respir Physiol Neurobiol 145:115-26. 2005
    ..Protonation of these residues may lead to a change in protein conformation that is coupled to a change in channel activity. Depending on the location of the protonation sites, a membrane protein can detect extra- and/or intracellular pH...
  14. ncbi Single nucleotide polymorphisms in K(ATP) channels: muscular impact on type 2 diabetes
    Li Li
    Department of Biology, Georgia State University, 24 Peachtree Center Ave, Atlanta, Georgia 30302 4010, USA
    Diabetes 54:1592-7. 2005
    ....
  15. ncbi Determinant role of membrane helices in K ATP channel gating
    R Wang
    Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303 4010, USA
    J Membr Biol 204:1-10. 2005
    ..1 channel, which is normally pH- insensitive. Thus, the manner in which the TM1 and TM2 helices interact appears to determine whether the channels are open or closed following ligand binding...
  16. ncbi Elimination of allosteric modulation of myocardial KATP channels by ATP and protons in two Kir6.2 polymorphisms found in sudden cardiac death
    Ningren Cui
    Department of Biology, Georgia State University, Atlanta, Georgia 30302 4010, USA
    Physiol Genomics 25:105-15. 2006
    ....
  17. ncbi Multicellular recordings of cultured brainstem neurons in microelectrode arrays
    Junda Su
    Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30302 4010, USA
    Cell Tissue Res 326:25-33. 2006
    ....
  18. ncbi Gating of the ATP-sensitive K+ channel by a pore-lining phenylalanine residue
    Asheebo Rojas
    Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30302 4010, USA
    Biochim Biophys Acta 1768:39-51. 2007
    ..Thus, it is likely that the Phe168 acts as not only a steric hindrance gate but also potentially a facilitator of gating transitions in the Kir6.2 channel...
  19. pmc High CO2 chemosensitivity versus wide sensing spectrum: a paradoxical problem and its solutions in cultured brainstem neurons
    Junda Su
    Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30302 4010, USA
    J Physiol 578:831-41. 2007
    ....
  20. ncbi Subunit-stoichiometric evidence for kir6.2 channel gating, ATP binding, and binding-gating coupling
    Runping Wang
    Department of Biology, Georgia State University, Atlanta, GA 30302 4010, USA
    Mol Pharmacol 71:1646-56. 2007
    ..No such preference was found between the C and N termini. These phenomena are well-described with the operational model used widely for ligand-receptor interactions...
  21. ncbi Arginine vasopressin inhibits Kir6.1/SUR2B channel and constricts the mesenteric artery via V1a receptor and protein kinase C
    Weiwei Shi
    Department of Biology, Georgia State University, 24 Peachtree Center Ave, Atlanta, GA 30302 4010, USA
    Am J Physiol Regul Integr Comp Physiol 293:R191-9. 2007
    ..These results therefore indicate that the Kir6.1/SUR2B channel is a target molecule of AVP, and the channel inhibition involves G(q)-coupled V1a receptor and PKC...
  22. ncbi Subunit stoichiometry of the Kir1.1 channel in proton-dependent gating
    Runping Wang
    Department of Biology, Georgia State University, Atlanta, Georgia 30302 4010, USA
    J Biol Chem 280:13433-41. 2005
    ....