Inhibitory Neural Regulation of the Ca Transients in Intramuscular Interstitial Cells of Cajal in the Small Intestine

Overview

Journal Front Physiol

Date 2018 Apr 25

PMID 29686622

Citations 23

Authors

Salah A Baker

Bernard T Drumm

Caroline A Cobine

Kathleen D Keef

Kenton M Sanders

Affiliations

Soon will be listed here.

Abstract

Gastrointestinal motility is coordinated by enteric neurons. Both inhibitory and excitatory motor neurons innervate the syncytium consisting of smooth muscle cells (SMCs) interstitial cells of Cajal (ICC) and PDGFRα cells (SIP syncytium). Confocal imaging of mouse small intestines from animals expressing GCaMP3 in ICC were used to investigate inhibitory neural regulation of ICC in the deep muscular plexus (ICC-DMP). We hypothesized that Ca signaling in ICC-DMP can be modulated by inhibitory enteric neural input. ICC-DMP lie in close proximity to the varicosities of motor neurons and generate ongoing Ca transients that underlie activation of Ca-dependent Cl channels and regulate the excitability of SMCs in the SIP syncytium. Electrical field stimulation (EFS) caused inhibition of Ca for the first 2-3 s of stimulation, and then Ca transients escaped from inhibition. The NO donor (DEA-NONOate) inhibited Ca transients and Nω-Nitro-L-arginine (L-NNA) or a guanylate cyclase inhibitor (ODQ) blocked inhibition induced by EFS. Purinergic neurotransmission did not affect Ca transients in ICC-DMP. Purinergic neurotransmission elicits hyperpolarization of the SIP syncytium by activation of K channels in PDGFRα cells. Generalized hyperpolarization of SIP cells by pinacidil (K agonist) or MRS2365 (P2Y1 agonist) also had no effect on Ca transients in ICC-DMP. Peptidergic transmitter receptors (VIP and PACAP) are expressed in ICC and can modulate ICC-DMP Ca transients. In summary Ca transients in ICC-DMP are blocked by enteric inhibitory neurotransmission. ICC-DMP lack a voltage-dependent mechanism for regulating Ca release, and this protects Ca handling in ICC-DMP from membrane potential changes in other SIP cells.

Citing Articles

Immunohistochemical characterization of interstitial cells and their spatial relationship to motor neurons within the mouse esophagus.

Ni Bhraonain E, Turner J, Hannigan K, Sanders K, Cobine C Cell Tissue Res. 2024; 399(1):61-84.

PMID: 39607495 DOI: 10.1007/s00441-024-03929-z.

Automated denoising software for calcium imaging signals using deep learning.

Kamran S, Moghnieh H, Hossain K, Bartlett A, Tavakkoli A, Drumm B Heliyon. 2024; 10(21):e39574.

PMID: 39524741 PMC: 11546308. DOI: 10.1016/j.heliyon.2024.e39574.

Interstitial cells of the sip syncytium regulate basal membrane potential in murine gastric corpus.

Hwang S, Kim M, Jones A, Basma N, Baker S, Sanders K FASEB J. 2024; 38(16):e23863.

PMID: 39143726 PMC: 11587931. DOI: 10.1096/fj.202400982R.

Immunohistochemical characterization of interstitial cells and their relationship to motor neurons within the mouse esophagus.

Ni Bhraonain E, Turner J, Hannigan K, Sanders K, Cobine C Res Sq. 2024; .

PMID: 38947055 PMC: 11213231. DOI: 10.21203/rs.3.rs-4474290/v1.

Modulation of intracellular calcium activity in interstitial cells of Cajal by inhibitory neural pathways within the internal anal sphincter.

Hannigan K, Ni Bhraonain E, Gould T, Keef K, Cobine C Am J Physiol Gastrointest Liver Physiol. 2024; 327(3):G382-G404.

PMID: 38860285 PMC: 11427099. DOI: 10.1152/ajpgi.00309.2023.

References

Huizinga J, Chen J, Zhu Y, Pawelka A, McGinn R, Bardakjian B . The origin of segmentation motor activity in the intestine. Nat Commun. 2014; 5:3326. PMC: 4885742. DOI: 10.1038/ncomms4326. View

Salmhofer H, Neuhuber W, Ruth P, Huber A, Russwurm M, Allescher H . Pivotal role of the interstitial cells of Cajal in the nitric oxide signaling pathway of rat small intestine. Morphological evidence. Cell Tissue Res. 2001; 305(3):331-40. DOI: 10.1007/s004410100410. View

Burns A, Lomax A, Torihashi S, Sanders K, Ward S . Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach. Proc Natl Acad Sci U S A. 1996; 93(21):12008-13. PMC: 38174. DOI: 10.1073/pnas.93.21.12008. View

Sanders K . Enteric Inhibitory Neurotransmission, Starting Down Under. Adv Exp Med Biol. 2016; 891:21-9. PMC: 8325941. DOI: 10.1007/978-3-319-27592-5_3. View

Zhou D, Komuro T . Interstitial cells associated with the deep muscular plexus of the guinea-pig small intestine, with special reference to the interstitial cells of Cajal. Cell Tissue Res. 1992; 268(2):205-16. DOI: 10.1007/BF00318788. View

Ekblad E, Jongsma H, Brabet P, Bockaert J, Sundler F . Characterization of intestinal receptors for VIP and PACAP in rat and in PAC1 receptor knockout mouse. Ann N Y Acad Sci. 2001; 921:137-47. DOI: 10.1111/j.1749-6632.2000.tb06960.x. View

BANKS B, Brown C, Burgess G, Burnstock G, Claret M, Cocks T . Apamin blocks certain neurotransmitter-induced increases in potassium permeability. Nature. 1979; 282(5737):415-7. DOI: 10.1038/282415a0. View

Iino S, Ward S, Sanders K . Interstitial cells of Cajal are functionally innervated by excitatory motor neurones in the murine intestine. J Physiol. 2004; 556(Pt 2):521-30. PMC: 1664950. DOI: 10.1113/jphysiol.2003.058792. View

Bult H, Boeckxstaens G, Pelckmans P, Jordaens F, Van Maercke Y, Herman A . Nitric oxide as an inhibitory non-adrenergic non-cholinergic neurotransmitter. Nature. 1990; 345(6273):346-7. DOI: 10.1038/345346a0. View

10.

Ward S, Burns A, Torihashi S, Sanders K . Mutation of the proto-oncogene c-kit blocks development of interstitial cells and electrical rhythmicity in murine intestine. J Physiol. 1994; 480 ( Pt 1):91-7. PMC: 1155780. DOI: 10.1113/jphysiol.1994.sp020343. View

11.

Shahi P, Choi S, Jeong Y, Park C, So I, Jun J . Basal cGMP regulates the resting pacemaker potential frequency of cultured mouse colonic interstitial cells of Cajal. Naunyn Schmiedebergs Arch Pharmacol. 2014; 387(7):641-8. DOI: 10.1007/s00210-014-0976-2. View

12.

Iino S, Horiguchi K, Nojyo Y . Interstitial cells of Cajal are innervated by nitrergic nerves and express nitric oxide-sensitive guanylate cyclase in the guinea-pig gastrointestinal tract. Neuroscience. 2008; 152(2):437-48. DOI: 10.1016/j.neuroscience.2007.12.044. View

13.

Xue L, Farrugia G, Miller S, Ferris C, Snyder S, Szurszewski J . Carbon monoxide and nitric oxide as coneurotransmitters in the enteric nervous system: evidence from genomic deletion of biosynthetic enzymes. Proc Natl Acad Sci U S A. 2000; 97(4):1851-5. PMC: 26525. DOI: 10.1073/pnas.97.4.1851. View

14.

Lies B, Beck K, Keppler J, Saur D, Groneberg D, Friebe A . Nitrergic signalling via interstitial cells of Cajal regulates motor activity in murine colon. J Physiol. 2015; 593(20):4589-601. PMC: 4606533. DOI: 10.1113/JP270511. View

15.

Sanders K, Ward S, Koh S . Interstitial cells: regulators of smooth muscle function. Physiol Rev. 2014; 94(3):859-907. PMC: 4152167. DOI: 10.1152/physrev.00037.2013. View

16.

Torihashi S, Kobayashi S, Gerthoffer W, Sanders K . Interstitial cells in deep muscular plexus of canine small intestine may be specialized smooth muscle cells. Am J Physiol. 1993; 265(4 Pt 1):G638-45. DOI: 10.1152/ajpgi.1993.265.4.G638. View

17.

Durnin L, Lees A, Manzoor S, Sasse K, Sanders K, Mutafova-Yambolieva V . Loss of nitric oxide-mediated inhibition of purine neurotransmitter release in the colon in the absence of interstitial cells of Cajal. Am J Physiol Gastrointest Liver Physiol. 2017; 313(5):G419-G433. PMC: 5792210. DOI: 10.1152/ajpgi.00045.2017. View

18.

DAntonio C, Wang B, Mckay C, Huizinga J . Substance P activates a non-selective cation channel in murine pacemaker ICC. Neurogastroenterol Motil. 2009; 21(9):985-e79. DOI: 10.1111/j.1365-2982.2009.01318.x. View

19.

Hwang S, Blair P, Durnin L, Mutafova-Yambolieva V, Sanders K, Ward S . P2Y1 purinoreceptors are fundamental to inhibitory motor control of murine colonic excitability and transit. J Physiol. 2012; 590(8):1957-72. PMC: 3573315. DOI: 10.1113/jphysiol.2011.224634. View

20.

Shuttleworth C, Xue C, Ward S, de Vente J, Sanders K . Immunohistochemical localization of 3',5'-cyclic guanosine monophosphate in the canine proximal colon: responses to nitric oxide and electrical stimulation of enteric inhibitory neurons. Neuroscience. 1993; 56(2):513-22. DOI: 10.1016/0306-4522(93)90350-o. View