Cyclic AMP signaling controls action potential firing rate and molecular circadian pacemaking in the suprachiasmatic nucleus

Atkinson, Susan E., Maywood, Elizabeth S., Chesham, Johanna E., Wozny, Christian, Colwell, Christopher S., Hastings, Michael H. and Williams, Stephen R. (2011) Cyclic AMP signaling controls action potential firing rate and molecular circadian pacemaking in the suprachiasmatic nucleus. Journal of Biological Rhythms, 26 3: 210-220. doi:10.1177/0748730411402810

Author Atkinson, Susan E.
Maywood, Elizabeth S.
Chesham, Johanna E.
Wozny, Christian
Colwell, Christopher S.
Hastings, Michael H.
Williams, Stephen R.
Title Cyclic AMP signaling controls action potential firing rate and molecular circadian pacemaking in the suprachiasmatic nucleus
Journal name Journal of Biological Rhythms   Check publisher's open access policy
ISSN 0748-7304
Publication date 2011-06-01
Sub-type Article (original research)
DOI 10.1177/0748730411402810
Open Access Status DOI
Volume 26
Issue 3
Start page 210
End page 220
Total pages 11
Place of publication Thousand Oaks, CA, United States
Publisher Sage Publications
Language eng
Subject 1314 Physiology
2737 Physiology (medical)
Abstract Circadian pacemaking in suprachiasmatic nucleus (SCN) neurons revolves around transcriptional/posttranslational feedback loops, driven by protein products of “clock” genes. These loops are synchronized and sustained by intercellular signaling, involving vasoactive intestinal peptide (VIP) via its VPAC2 receptor, which positively regulates cAMP synthesis. In turn, SCN cells communicate circadian time to the brain via a daily rhythm in electrophysiological activity. To investigate the mechanisms whereby VIP/VPAC2/cAMP signaling controls SCN molecular and electrical pacemaking, we combined bioluminescent imaging of circadian gene expression and whole-cell electrophysiology in organotypic SCN slices. As a potential direct target of cAMP, we focused on hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. Mutations of VIP-ergic signaling compromised the SCN molecular pacemaker, diminishing the amplitude and intercellular synchrony of circadian gene expression. These deficits were transiently reversed by elevation of cAMP. Similarly, cellular synchrony in electrical firing rates was lost in SCN slices lacking the VPAC2 receptor for VIP. Whole-cell current-clamp recordings in wild-type (WT) slices revealed voltage responses shaped by the conductance Ih, which is mediated by HCN channel activity. The influence of Ih on voltage responses showed a modest peak in early circadian day, identifying HCN channels as a putative mediator of cAMP-dependent circadian effects on firing rate. Ih, however, was unaffected by loss of VIP-ergic signaling in VPAC2-null slices, and inhibition of cAMP synthesis had no discernible effect on Ih but did suppress gene expression and SCN firing rates. Moreover, only sustained but not acute, pharmacological blockade of HCN channels reduced action potential (AP) firing. Thus, our evidence suggests that in the SCN, cAMP-mediated signaling is not a principal regulator of HCN channel function and that HCN is not a determinant of AP firing rate. VIP/cAMP-dependent signaling sustains the SCN molecular oscillator and action potential firing via mechanisms yet to be identified.
Keyword cAMP
HCN channel
Ih conductance
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2012 Collection
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Citation counts: TR Web of Science Citation Count  Cited 23 times in Thomson Reuters Web of Science Article | Citations
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Created: Fri, 21 Oct 2011, 03:14:11 EST by Stephen Williams on behalf of Queensland Brain Institute