Abstract:
:Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are key modulators of neuronal activity by providing the depolarizing cation current I(h) involved in rhythmogenesis, dendritic integration, and synaptic transmission. These tasks critically depend on the availability of HCN channels, which is dynamically regulated by intracellular cAMP; the range of this regulation, however, largely differs among neurons in the mammalian brain. Using affinity purification and high-resolution mass spectrometry, we identify the PEX5R/Trip8b protein as the beta subunit of HCN channels in the mammalian brain. Coassembly of PEX5R/Trip8b affects HCN channel gating in a subtype-dependent and mode-specific way: activation of HCN2 and HCN4 by cAMP is largely impaired, while gating by phosphoinositides and basal voltage-dependence remain unaffected. De novo expression of PEX5R/Trip8b in cardiomyocytes abolishes beta-adrenergic stimulation of HCN channels. These results demonstrate that PEX5R/Trip8b is an intrinsic auxiliary subunit of brain HCN channels and establish HCN-PEX5R/Trip8b coassembly as a mechanism to control the channels' responsiveness to cyclic nucleotide signaling.
journal_name
Neuronjournal_title
Neuronauthors
Zolles G,Wenzel D,Bildl W,Schulte U,Hofmann A,Müller CS,Thumfart JO,Vlachos A,Deller T,Pfeifer A,Fleischmann BK,Roeper J,Fakler B,Klöcker Ndoi
10.1016/j.neuron.2009.05.008subject
Has Abstractpub_date
2009-06-25 00:00:00pages
814-25issue
6eissn
0896-6273issn
1097-4199pii
S0896-6273(09)00359-6journal_volume
62pub_type
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