2mpf Citations

Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function.


cAMP signaling in the brain mediates several higher order neural processes. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels directly bind cAMP through their cytoplasmic cyclic nucleotide binding domain (CNBD), thus playing a unique role in brain function. Neuronal HCN channels are also regulated by tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), an auxiliary subunit that antagonizes the effects of cAMP by interacting with the channel CNBD. To unravel the molecular mechanisms underlying the dual regulation of HCN channel activity by cAMP/TRIP8b, we determined the NMR solution structure of the HCN2 channel CNBD in the cAMP-free form and mapped on it the TRIP8b interaction site. We reconstruct here the full conformational changes induced by cAMP binding to the HCN channel CNBD. Our results show that TRIP8b does not compete with cAMP for the same binding region; rather, it exerts its inhibitory action through an allosteric mechanism, preventing the cAMP-induced conformational changes in the HCN channel CNBD.

Articles - 2mpf mentioned but not cited (2)

  1. Structure of a eukaryotic cyclic-nucleotide-gated channel. Li M, Zhou X, Wang S, Michailidis I, Gong Y, Su D, Li H, Li X, Yang J. Nature 542 60-65 (2017)
  2. Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function. Saponaro A, Pauleta SR, Cantini F, Matzapetakis M, Hammann C, Donadoni C, Hu L, Thiel G, Banci L, Santoro B, Moroni A. Proc. Natl. Acad. Sci. U.S.A. 111 14577-14582 (2014)

Reviews citing this publication (2)

  1. Structural insights into the mechanisms of CNBD channel function. James ZM, Zagotta WN. J. Gen. Physiol. 150 225-244 (2018)
  2. HCN Channels Modulators: The Need for Selectivity. Novella Romanelli M, Sartiani L, Masi A, Mannaioni G, Manetti D, Mugelli A, Cerbai E. Curr Top Med Chem 16 1764-1791 (2016)

Articles citing this publication (26)

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  4. Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides. DeBerg HA, Brzovic PS, Flynn GE, Zagotta WN, Stoll S. J. Biol. Chem. 291 371-381 (2016)
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  7. Research Support, Non-U.S. Gov't Animal models suggest the TRIP8b-HCN interaction is a therapeutic target for major depressive disorder. Lyman KA, Han Y, Chetkovich DM. Expert Opin. Ther. Targets 21 235-237 (2017)
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  11. Ligand binding and activation properties of the purified bacterial cyclic nucleotide-gated channel SthK. Schmidpeter PAM, Gao X, Uphadyay V, Rheinberger J, Nimigean CM. J. Gen. Physiol. 150 821-834 (2018)
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  15. Fusicoccin Activates KAT1 Channels by Stabilizing Their Interaction with 14-3-3 Proteins. Saponaro A, Porro A, Chaves-Sanjuan A, Nardini M, Rauh O, Thiel G, Moroni A, Moroni A. Plant Cell 29 2570-2580 (2017)
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  24. Inherited macular degeneration-associated mutations in CNGB3 increase the ligand sensitivity and spontaneous open probability of cone cyclic nucleotide-gated channels. Meighan PC, Peng C, Varnum MD. Front Physiol 6 177 (2015)
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  26. Mechanical transduction of cytoplasmic-to-transmembrane-domain movements in a hyperpolarization-activated cyclic nucleotide-gated cation channel. Gross C, Saponaro A, Santoro B, Moroni A, Thiel G, Hamacher K. J. Biol. Chem. 293 12908-12918 (2018)