Regulated expression of HCN channels and cAMP levels shape the properties of the h current in developing rat hippocampus.
The hyperpolarization-activated current (I(h)) contributes to intrinsic properties and network responses of neurons. Its biophysical properties depend on the expression profiles of the underlying hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels and the presence of cyclic AMP (cAMP) that potently and differentially modulates I(h) conducted by HCN1, HCN2 and/or HCN4. Here, we studied the properties of I(h) in hippocampal CA1 pyramidal cells, the developmental evolution of the HCN-subunit isoforms that contribute to this current, and their interplay with age-dependent free cAMP concentrations, using electrophysiological, molecular and biochemical methods. I(h) amplitude increased progressively during the first four postnatal weeks, consistent with the observed overall increased expression of HCN channels. Activation kinetics of the current accelerated during this period, consonant with the quantitative reduction of mRNA and protein expression of the slow-kinetics HCN4 isoform and increased levels of HCN1. The sensitivity of I(h) to cAMP, and the contribution of the slow component to the overall I(h), decreased with age. These are likely a result of the developmentally regulated transition of the complement of HCN channel isoforms from cAMP sensitive to relatively cAMP insensitive. Thus, although hippocampal cAMP concentrations increased over twofold during the developmental period studied, the coordinated changes in expression of three HCN channel isoforms resulted in reduced effects of this signalling molecule on neuronal h currents.
Surges
Rainer
R
Department of Neurology, University Clinics Freiburg, Breisacher Strasse 64, 79106 Freiburg, Germany. rainer.surges@uniklinik-freiburg.de
Brewster
Amy L
AL
Bender
Roland A
RA
Beck
Heinz
H
Feuerstein
Thomas J
TJ
Baram
Tallie Z
TZ
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000242:Cyclic AMP / Q000378:metabolism*; D054815:Cyclic Nucleotide-Gated Cation Channels; D005260:Female; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D066298:In Vitro Techniques; D007473:Ion Channels / Q000096:biosynthesis / Q000502:physiology*; D008297:Male; D018408:Patch-Clamp Techniques; D015221:Potassium Channels; D020033:Protein Isoforms / Q000096:biosynthesis / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D054815:Cyclic Nucleotide-Gated Cation Channels; C578667:Hcn1 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels; D020033:Protein Isoforms; D000242:Cyclic AMP