Propulsive colonic contractions are mediated by inhibition-driven poststimulus responses that originate in interstitial cells of Cajal.
Propulsive colonic contractions are mediated by inhibition-driven poststimulus responses that originate in interstitial cells of Cajal.
复制标题
推进性结肠收缩由起源于卡哈尔间质细胞的抑制驱动的刺激后反应介导。
DOI：
10.1073/pnas.2123020119
复制
发表时间：
2022-05-03
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
肠蠕动反射引起结肠移行运动复合体（CMMCs），被认为是由肠兴奋性神经元刺激平滑肌细胞（SMCs）产生的。我们发现，阿托品并没有阻止CMMCs和提出一个概念，表明刺激后兴奋性反应后，氮能反应的Cajal间质细胞（ICC）负责启动CMMCs。氮能刺激可抑制ICC中的Ca ~（2+）瞬变。在抑制期后，Ca 2+瞬变增加，激活传导至SMC的电流并启动传播性收缩。ICC产生的后刺激激发解释了CMMCs的性质。这一点很重要，因为目前结肠转运的治疗操作通常针对加强胆碱能反应，而靶向氮能反应可能更合适。蠕动反射是胃肠道的基本行为，其中粘膜刺激激活推进性收缩。反射通过用肌间神经丛中的细胞体刺激内在初级传入神经元并投射到固有层、通过中间神经元分配信息以及激活肌肉运动神经元而发生。目前的概念是，兴奋性胆碱能运动神经元被激活的近端和抑制性神经元被激活的刺激部位的远端。我们发现，阿托品减少，但不阻止，结肠移行运动复合体（CMMCs）在小鼠，猴子和人的结肠，这表明一个机制以外的胆碱能神经元激活参与CMMCs的生成/传播。CMMCs被激活后，一段时间的神经刺激在每个物种的结肠，这表明CMMCs的推进收缩可能是由于刺激后的兴奋，抑制性神经反应。阻断氮能神经传递可抑制肌肉条的刺激后兴奋，并阻断完整结肠中的CMMCs。我们的数据表明，刺激后的兴奋是由于增加Ca 2+瞬变在结肠间质细胞的Cajal（ICC）停止氮能，环磷酸鸟苷（cGMP）依赖性抑制反应。氮能反应后Ca 2+瞬变的增加激活了ICC中由Ano 1编码的Ca 2+激活的Cl−电导。ANO 1通道的拮抗剂抑制结肠肌肉和完整结肠中CMMCs的刺激后去极化。ICC的刺激后兴奋性反应与cGMP抑制的环磷酸腺苷（cAMP）磷酸二酯酶3a和cAMP依赖性效应有关。这些数据表明CMMCs在结肠中产生和繁殖的替代机制。
The peristaltic reflex elicits colonic migrating motor complexes (CMMCs) that are thought to be generated by enteric excitatory neurons stimulating smooth muscle cells (SMCs). We found that atropine did not block CMMCs and present a concept showing that poststimulus excitatory responses following nitrergic responses in interstitial cells of Cajal (ICC) are responsible for initiation of CMMCs. Ca2+ transients in ICC are inhibited by nitrergic stimulation. After the inhibitory period, Ca2+ transients are increased, activating currents that are conducted to SMCs and initiate propagated contractions. Poststimulus excitation generated by ICC explains the properties of CMMCs. This is important because current therapeutic manipulation of colonic transit is typically directed at strengthening cholinergic responses, whereas targeting nitrergic responses may be more suitable. The peristaltic reflex is a fundamental behavior of the gastrointestinal (GI) tract in which mucosal stimulation activates propulsive contractions. The reflex occurs by stimulation of intrinsic primary afferent neurons with cell bodies in the myenteric plexus and projections to the lamina propria, distribution of information by interneurons, and activation of muscle motor neurons. The current concept is that excitatory cholinergic motor neurons are activated proximal to and inhibitory neurons are activated distal to the stimulus site. We found that atropine reduced, but did not block, colonic migrating motor complexes (CMMCs) in mouse, monkey, and human colons, suggesting a mechanism other than one activated by cholinergic neurons is involved in the generation/propagation of CMMCs. CMMCs were activated after a period of nerve stimulation in colons of each species, suggesting that the propulsive contractions of CMMCs may be due to the poststimulus excitation that follows inhibitory neural responses. Blocking nitrergic neurotransmission inhibited poststimulus excitation in muscle strips and blocked CMMCs in intact colons. Our data demonstrate that poststimulus excitation is due to increased Ca2+ transients in colonic interstitial cells of Cajal (ICC) following cessation of nitrergic, cyclic guanosine monophosphate (cGMP)-dependent inhibitory responses. The increase in Ca2+ transients after nitrergic responses activates a Ca2+-activated Cl− conductance, encoded by Ano1, in ICC. Antagonists of ANO1 channels inhibit poststimulus depolarizations in colonic muscles and CMMCs in intact colons. The poststimulus excitatory responses in ICC are linked to cGMP-inhibited cyclic adenosine monophosphate (cAMP) phosphodiesterase 3a and cAMP-dependent effects. These data suggest alternative mechanisms for generation and propagation of CMMCs in the colon.
登录
查看更多内容
影响因子：
5.5
作者：
BENNETT, MR
通讯作者：
BENNETT, MR
影响因子：
4.6
作者：
Drumm, Bernard T.;Rembetski, Benjamin E.;Sanders, Kenton M.
通讯作者：
Sanders, Kenton M.
影响因子：
2
作者：
Faussone-Pellegrini, MS;Infantino, A;Lise, M
通讯作者：
Lise, M
影响因子：
7.3
作者：
Franck, H;Sweeney, KM;Shuttleworth, CWR
通讯作者：
Shuttleworth, CWR
影响因子：
3.5
作者：
Bayguinov, P. O.;Broadhead, M. J.;Smith, T. K.
通讯作者：
Smith, T. K.