Kurahashi Masaaki, Baker Salah A, Kito Yoshihiko, Bartlett Allison, Hara Masayasu, Takeyama Hiromitsu, Hashitani Hikaru, Sanders Kenton M
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Iowa, Iowa City, Iowa, USA.
Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada, USA.
Cell Mol Gastroenterol Hepatol. 2022;14(2):357-373. doi: 10.1016/j.jcmgh.2022.05.004. Epub 2022 May 13.
BACKGROUND & AIMS: Platelet-derived growth factor receptor α (PDGFRα)-positive interstitial cells (PIC) are interposed between enteric nerve fibers and smooth muscle cells (SMCs) in the tunica muscularis of the gastrointestinal tract. PIC have robust expression of small conductance Ca activated K channels 3 (SK3 channels) and transduce inhibitory inputs from purinergic and sympathetic nerves in mouse and human colon. We investigated whether PIC also express pituitary adenylate cyclase-activating polypeptide (PACAP) receptors, PAC1 (PACR), and are involved in mediating inhibitory regulation of colonic contractions by PACAP in mouse and human colons.
Gene expression analysis, Ca imaging, and contractile experiments were performed on mouse colonic muscles. Ca imaging, intracellular electrical recordings, and contractile experiments were performed on human colonic muscles.
Adcyap1r1 (encoding PACR) is highly expressed in mouse PIC. Interstitial cells of Cajal (ICC) and SMCs expressed far lower levels of Adcyap1r. Vipr1 and Vipr2 were expressed at low levels in PIC, ICC, and SMCs. PACAP elicited Ca transients in mouse PIC and inhibited spontaneous phasic contractions via SK channels. In human colonic muscles, PACR agonists elicited Ca transients in PIC, hyperpolarized SMCs through SK channels and inhibited spontaneous phasic contractions.
PIC of mouse and human colon utilize PACR-SK channel signal pathway to inhibit colonic contractions in response to PACAP. Effects of PACAP are in addition to the previously described purinergic and sympathetic inputs to PIC. Thus, PIC integrate inhibitory inputs from at least 3 neurotransmitters and utilize several types of receptors to activate SK channels and regulate colonic contractile behaviors.
血小板衍生生长因子受体α（PDGFRα）阳性间质细胞（PIC）介于胃肠道肌层的肠神经纤维与平滑肌细胞（SMC）之间。PIC有强大的小电导钙激活钾通道3（SK3通道）表达，并在小鼠和人类结肠中转导来自嘌呤能和交感神经的抑制性输入。我们研究了PIC是否也表达垂体腺苷酸环化酶激活多肽（PACAP）受体PAC1（PACR），以及是否参与介导PACAP对小鼠和人类结肠收缩的抑制调节。
对小鼠结肠肌肉进行基因表达分析、钙成像和收缩实验。对人类结肠肌肉进行钙成像、细胞内电记录和收缩实验。
Adcyap1r1（编码PACR）在小鼠PIC中高度表达。 Cajal间质细胞（ICC）和平滑肌细胞中Adcyap1r的表达水平要低得多。Vipr1和Vipr2在PIC、ICC和平滑肌细胞中的表达水平较低。PACAP在小鼠PIC中引发钙瞬变，并通过SK通道抑制自发性相性收缩。在人类结肠肌肉中，PACR激动剂在PIC中引发钙瞬变，通过SK通道使平滑肌细胞超极化，并抑制自发性相性收缩。
小鼠和人类结肠的PIC利用PACR-SK通道信号通路来抑制结肠收缩以响应PACAP。PACAP的作用除了先前描述的对PIC的嘌呤能和交感神经输入之外。因此，PIC整合来自至少3种神经递质的抑制性输入，并利用几种类型的受体来激活SK通道并调节结肠收缩行为。
