ells in most tissues are interconnected by gap junction channels, which allow the passage of electrolytes and small molecules from cell to cell. In some excitable cells these channels are involved in electrical synaptic transmission and/or synchronization of electrical activity. In other tissues they are thought to pass signal molecules and to couple the cells metabolically. In addition, as recent evidence suggests, some gap unction proteins also form functional hemichannels, that under special circumstances, transiently connect the cytoplasm with the extracellular space. Thus, gap junction proteins may mediate extracellular communication in addition to their classical role of direct cell-to-cell communication. The objective of this research project is to understand the permeation of small ions and molecules including second messengers through gap junction channels and hemichannels formed by pannexin 1. Pannexin 1 is a member of a recently discovered small family of proteins in vertebrates including humans capable of forming hemichannels and gap junction channels in addition to the well characterized connexin family. The first specific aim tests the hypothesis that the selective permeabilities of the channels formed by connexins and pannexins are distinct and thus enable different functions of these proteins. The pore dimensions of pannexin channels will be determined and compared to those of connexin channels.
The second aim tests the hypothesis that connexins and pannexins form channels of generally similar structure with respect to membrane topology and location of pore forming moieties despite a lack of sequence homology.
The third aim i s to identify moieties in the pannexin 1 sequence mediating calcium sensitivity. Pannexin channels are activated by cytoplasmic calcium in the micromolar concentration range which contrasts the inhibition or insensitivity of connexin channels to calcium. Gap junction channels are known to be associated with a series of human diseases. Understanding their molecular function is therefore relevant to the diagnosis and therapy of the diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM048610-16
Application #
7741255
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Rivera-Rentas, Alberto L
Project Start
1993-01-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
16
Fiscal Year
2010
Total Cost
$323,013
Indirect Cost
Name
University of Miami School of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Samuels, Stuart E; Lipitz, Jeffrey B; Wang, Junjie et al. (2013) Arachidonic acid closes innexin/pannexin channels and thereby inhibits microglia cell movement to a nerve injury. Dev Neurobiol 73:621-31
Dahl, Gerhard; Qiu, Feng; Wang, Junjie (2013) The bizarre pharmacology of the ATP release channel pannexin1. Neuropharmacology 75:583-93
Dahl, Gerhard; Keane, Robert W (2012) Pannexin: from discovery to bedside in 11±4 years? Brain Res 1487:150-9
Qiu, Feng; Wang, Junjie; Spray, David C et al. (2011) Two non-vesicular ATP release pathways in the mouse erythrocyte membrane. FEBS Lett 585:3430-5
Ambrosi, Cinzia; Gassmann, Oliver; Pranskevich, Jennifer N et al. (2010) Pannexin1 and Pannexin2 channels show quaternary similarities to connexons and different oligomerization numbers from each other. J Biol Chem 285:24420-31
Samuels, Stuart E; Lipitz, Jeffrey B; Dahl, Gerhard et al. (2010) Neuroglial ATP release through innexin channels controls microglial cell movement to a nerve injury. J Gen Physiol 136:425-42
Wang, Junjie; Dahl, Gerhard (2010) SCAM analysis of Panx1 suggests a peculiar pore structure. J Gen Physiol 136:515-27
Qiu, Feng; Dahl, Gerhard (2009) A permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATP. Am J Physiol Cell Physiol 296:C250-5
Bunse, Stefanie; Locovei, Silviu; Schmidt, Matthias et al. (2009) The potassium channel subunit Kvbeta3 interacts with pannexin 1 and attenuates its sensitivity to changes in redox potentials. FEBS J 276:6258-70
Ransford, George A; Fregien, Nevis; Qiu, Feng et al. (2009) Pannexin 1 contributes to ATP release in airway epithelia. Am J Respir Cell Mol Biol 41:525-34

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