Loss of HCN2 leads to delayed gastrointestinal motility and reduced energy intake in mice

Daniel W. Fisher, Phillip Luu, Neha Agarwal, Jonathan Kurz, Dane M. Chetkovich*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are important regulators of excitability in neural, cardiac, and other pacemaking cells, which are often altered in disease. In mice, loss of HCN2 leads to cardiac dysrhythmias, persistent spike-wave discharges similar to those seen in absence epilepsy, ataxia, tremor, reduced neuropathic and inflammatory pain, antidepressant-like behavior, infertility, and severely restricted growth. While many of these phenotypes have tissue-specific mechanisms, the cause of restricted growth in HCN2 knockout animals remains unknown. Here, we characterize a novel, 3kb insertion mutation of Hcn2 in the Tremor and Reduced Lifespan 2 (TRLS/2J) mouse that leads to complete loss of HCN2 protein, and we show that this mutation causes many phenotypes similar to other mice lacking HCN2 expression. We then demonstrate that while TRLS/2J mice have low blood glucose levels and impaired growth, dysfunction in hormonal secretion from the pancreas, pituitary, and thyroid are unlikely to lead to this phenotype. Instead, we find that homozygous TRLS/2J mice have abnormal gastrointestinal function that is characterized by less food consumption and delayed gastrointestinal transit as compared to wildtype mice. In summary, a novel mutation in HCN2 likely leads to impaired GI motility, causing the severe growth restriction seen in mice with mutations that eliminate HCN2 expression.

Original languageEnglish (US)
Article numbere0193012
JournalPloS one
Volume13
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

gastrointestinal motility
Gastrointestinal Motility
Energy Intake
energy intake
mice
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
mutation
Tremor
Growth
Phenotype
phenotype
Mutation
Antidepressive Agents
Blood Glucose
Animals
Gastrointestinal Transit
gastrointestinal transit
Absence Epilepsy
cyclic nucleotides
antidepressants

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Fisher, Daniel W. ; Luu, Phillip ; Agarwal, Neha ; Kurz, Jonathan ; Chetkovich, Dane M. / Loss of HCN2 leads to delayed gastrointestinal motility and reduced energy intake in mice. In: PloS one. 2018 ; Vol. 13, No. 2.
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Loss of HCN2 leads to delayed gastrointestinal motility and reduced energy intake in mice. / Fisher, Daniel W.; Luu, Phillip; Agarwal, Neha; Kurz, Jonathan; Chetkovich, Dane M.

In: PloS one, Vol. 13, No. 2, e0193012, 01.02.2018.

Research output: Contribution to journalArticle

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