Loss of HCN2 leads to delayed gastrointestinal motility and reduced energy intake in mice.
Loss of HCN2 leads to delayed gastrointestinal motility and reduced energy intake in mice.
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DOI：
10.1371/journal.pone.0193012
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Chetkovich DM
中科院分区：
文献类型：
--
作者：
Fisher DW;Luu P;Agarwal N;Kurz JE;Chetkovich DM
超极化激活的环核苷酸门控(HCN)通道是神经、心脏和其他起搏细胞兴奋性的重要调节因子，这些细胞在疾病中经常发生变化。在小鼠中，失去hcn2会导致心律失常、持续的棘波放电，类似于缺席癫痫、共济失调、震颤、神经病理性和炎症性疼痛减轻、抗抑郁药样行为、不孕不育和严重限制生长。虽然这些表型中的许多都有组织特异性的机制，但在HCN2基因敲除动物中限制生长的原因仍不清楚。在这里，我们描述了震颤和寿命减少2(TRLS/2J)小鼠中一种新型的3kb插入突变，该突变导致HCN2蛋白完全丧失，我们表明该突变导致许多表型类似于其他缺乏HCN2表达的小鼠。然后我们证明，虽然TRLS/2J小鼠血糖水平低，生长受损，但胰腺、脑下垂体和甲状腺的激素分泌功能障碍不太可能导致这种表型。相反，我们发现纯合子TRLS/2J小鼠具有异常的胃肠功能，其特征是与野生型小鼠相比，食物消耗更少，胃肠道转运延迟。综上所述，一种新的hcn2基因突变可能导致胃肠动力受损，导致在携带消除hcn2基因表达突变的小鼠中出现的严重生长受限。
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.
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影响因子：
--
作者：
Johnson, Kenneth R.;Marden, Coleen C.;Donahue, Leah Rae
通讯作者：
Donahue, Leah Rae
影响因子：
--
作者：
Kretschmannova, Karla;Kucka, Marek;Stojilkovic, Stanko S.
通讯作者：
Stojilkovic, Stanko S.
影响因子：
11.4
作者：
Ludwig, A;Budde, T;Hofmann, F
通讯作者：
Hofmann, F
影响因子：
6.1
作者：
Chung WK;Shin M;Jaramillo TC;Leibel RL;LeDuc CA;Fischer SG;Tzilianos E;Gheith AA;Lewis AS;Chetkovich DM
通讯作者：
Chetkovich DM
DOI：
10.4161/chan.4.3.11630
发表时间：
2010-05
期刊：
Channels (Austin, Tex.)
影响因子：
--
作者：
Lewis AS;Estep CM;Chetkovich DM
通讯作者：
Chetkovich DM