As an early event in CO2 sensing, changes in membrane excitability have been demonstrated in brainstem CO2 chemo sensitive neurons, which seem to result from alternations in synaptic transmission, transporter activity and/or ion channel activation. Indeed, studies including ours have shown that K+ channels are the key players in controlling membrane excitability in these chemo sensitive neurons. We have found that the hypercapnia-induced depolarization is attenuated by antagonism of K+ channels, while blockade of synaptic transmission and several other ion channels has no effect. We have thereafter studied these CO2-sensitive K+ channels and demonstrated a novel CO2 sensing mechanism in these channels. This mechanism relies on the inherent pH-sensing and channel-gating processes of inward rectifier K+ channels, allowing the change in PCO2 levels to be coupled to a nonexpanding change in membrane excitability. Among these CO2-sensitive K+ channels, the heteromeric Kir4.1-Kir5.1 is particularly interesting. With a linear working range at physiologic pH levels, these channels can detect both hypercapnia and hypocapnia. These plus their brainstem-specific expression make them the highly promising candidates for the potential CO2 sensing molecules in the central CO2 chemoreceptors. Clearly, detailed studies of the molecular mechanisms underlying the CO2 sensing in these K+ channels may yield important information of CO2 chemoreception. Thus, we have proposed experiments to test three specific hypotheses: 1) the heteromeric Kir4.1 -Kir5.1 channels act as CO2 sensors 2) the Kir4.1 -Kir5.1 channels are specifically expressed in brainstem neurons; and 3) CO2 enhances membrane excitability of chemo sensitive neurons by inhibiting the Kir4.1 -Kir5.1 channels. The outcome of these studies will not only improve our understanding of CO2 chemo receptive physiology but also may help the design of medical interventions by manipulating these cellular inherent CO2-sensing and responding mechanisms in the treatment and prevention of certain illnesses that are related to the CO2 sensation and modulation in central and peripheral cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL058410-05A1
Application #
6333178
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Program Officer
Twery, Michael
Project Start
1996-09-01
Project End
2005-02-28
Budget Start
2001-04-01
Budget End
2002-02-28
Support Year
5
Fiscal Year
2001
Total Cost
$214,500
Indirect Cost
Name
Georgia State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Cui, Ningren; Li, Li; Wang, Xueren et al. (2006) Elimination of allosteric modulation of myocardial KATP channels by ATP and protons in two Kir6.2 polymorphisms found in sudden cardiac death. Physiol Genomics 25:105-15
Su, Junda; Jiang, Chun (2006) Multicellular recordings of cultured brainstem neurons in microelectrode arrays. Cell Tissue Res 326:25-33
Li, Li; Shi, Yun; Wang, Xueren et al. (2005) Single nucleotide polymorphisms in K(ATP) channels: muscular impact on type 2 diabetes. Diabetes 54:1592-7
Wang, R; Rojas, A; Wu, J et al. (2005) Determinant role of membrane helices in K ATP channel gating. J Membr Biol 204:1-10
Wang, Runping; Su, Junda; Wang, Xueren et al. (2005) Subunit stoichiometry of the Kir1.1 channel in proton-dependent gating. J Biol Chem 280:13433-41
Jiang, Chun; Rojas, Asheebo; Wang, Runping et al. (2005) CO2 central chemosensitivity: why are there so many sensing molecules? Respir Physiol Neurobiol 145:115-26
Wu, J; Xu, H; Shen, W et al. (2004) Expression and coexpression of CO2-sensitive Kir channels in brainstem neurons of rats. J Membr Biol 197:179-91
Wu, Jianping; Piao, Hailan; Rojas, Asheebo et al. (2004) Critical protein domains and amino acid residues for gating the KIR6.2 channel by intracellular ATP. J Cell Physiol 198:73-81
Li, Li; Rojas, Asheebo; Wu, Jianping et al. (2004) Disruption of glucose sensing and insulin secretion by ribozyme Kir6.2-gene targeting in insulin-secreting cells. Endocrinology 145:4408-14
Mao, Jinzhe; Wang, Xueren; Chen, Fuxue et al. (2004) Molecular basis for the inhibition of G protein-coupled inward rectifier K(+) channels by protein kinase C. Proc Natl Acad Sci U S A 101:1087-92

Showing the most recent 10 out of 33 publications