Activity-dependent regulation of HCN pacemaker channels by cyclic AMP: signaling through dynamic allosteric coupling.
Signal transduction in neurons is a dynamic process, generally thought to be driven by transient changes in the concentration of second messengers. Here we describe a novel regulatory mechanism in which the dynamics of signaling through cyclic AMP are mediated by activity-dependent changes in the affinity of the hyperpolarization-activated, cation nonselective (HCN) channels for cAMP, rather than by changes in cAMP concentration. Due to the allosteric coupling of channel opening and ligand binding, changes in cellular electrical activity that alter the opening of the HCN channels modify the binding of static, basal levels of cAMP. These changes in ligand binding produce long-lasting changes in channel function which can contribute to the regulation of rhythmic firing patterns.
Wang
Jing
J
Integrated Program in Cellular, Molecular, and Biophysical Studies, Columbia University, 722 West 168 Street, New York, NY 10032, USA.
Chen
Shan
S
Nolan
Matthew F
MF
Siegelbaum
Steven A
SA
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008959:Models, Neurological; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism*; D009434:Neural Pathways / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009865:Oocytes; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013788:Thalamus / Q000378:metabolism; D014982:Xenopus laevis
D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins; D000242:Cyclic AMP