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

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.

Mutants of the Zebrafish K+ Channel Hcn2b Exhibit Epileptic-like Behaviors

“…The homozygous mutation of hcn2b generated here, hcn2b −/− , does not cause apparent morphological changes, since the animals presented normal length, mobility, and pigmentation. Although we did not monitor the weight nor the length of adult fish, we did not observe impaired growth with respect to the WT control as reported in mice [ 29 ]. However, during their lifetime, the mutants exhibited a higher rate of mortality.…”

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: An Emerging Role in Neurodegenerative Diseases

“…In addition to the possible role of HCN channels and their auxiliary subunit in depression-like behavior, a possible link between HCN channels and the olfactory, sleep, and gastrointestinal functions in animal models is also noteworthy (Sun et al, 2003; Fried et al, 2010; Alicia et al, 2012; Wang et al, 2012; Shahi et al, 2014; Hu et al, 2016; Fisher et al, 2018). Because of the important diagnostic and therapeutic value of these non-motor symptoms in PD, perhaps the above studies provide a new perspective for further exploration of PD.…”

Cohesin-protein Shugoshin-1 controls cardiac automaticity via HCN4 pacemaker channel

“…Interstitial Cells of Cajal, which function as pacemaker cells in the gut, also express HCN4, which has been reported to be a selective marker for this cell-type in mice 43 . There is evidence that intact HCN2 is required for normal intestinal peristalsis in a genetically-defined mouse model and that HCN4 is required for retrograde peristalsis in zebrafish 44 , 45 . Further work is needed to clarify whether SGO1 interacts with intestinal HCN channels and, if so, whether disruption of this interaction might contribute to the intestinal pseudo-obstruction component of CAID syndrome.…”