Dataset Information

PDGFRα⁺ Interstitial Cells are Effector Cells of PACAP Signaling in Mouse and Human Colon.

ABSTRACT:

Background & aims

Platelet-derived growth factor receptor α (PDGFRα)-positive interstitial cells (PICs) are interposed between enteric nerve fibers and smooth muscle cells (SMCs) in the tunica muscularis of the gastrointestinal tract. PICs have robust expression of small conductance Ca²⁺ activated K⁺ channels 3 (SK3 channels) and transduce inhibitory inputs from purinergic and sympathetic nerves in mouse and human colon. We investigated whether PICs also express pituitary adenylate cyclase-activating polypeptide (PACAP) receptors, PAC1 (PAC₁R), and are involved in mediating inhibitory regulation of colonic contractions by PACAP in mouse and human colons.

Methods

Gene expression analysis, Ca²⁺ imaging, and contractile experiments were performed on mouse colonic muscles. Ca²⁺ imaging, intracellular electrical recordings, and contractile experiments were performed on human colonic muscles.

Results

Adcyap1r1 (encoding PAC₁R) is highly expressed in mouse PICs. Interstitial cells of Cajal and SMCs expressed far lower levels of Adcyap1r. Vipr1 and Vipr2 were expressed at low levels in PICs, interstitial cells of Cajal, and SMCs. PACAP elicited Ca²⁺ transients in mouse PICs and inhibited spontaneous phasic contractions via SK channels. In human colonic muscles, PAC₁R agonists elicited Ca²⁺ transients in PIC, hyperpolarized SMCs through SK channels and inhibited spontaneous phasic contractions.

Conclusions

PICs of mouse and human colon utilize PAC₁R-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 PICs. Thus, PICs integrate inhibitory inputs from at least 3 neurotransmitters and utilize several types of receptors to activate SK channels and regulate colonic contractile behaviors.

SUBMITTER: Kurahashi M

PROVIDER: S-EPMC9250024 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Key pointsColonic intramuscular interstitial cells of Cajal (ICC-IM) exhibit spontaneous Ca2+ transients manifesting as stochastic events from multiple firing sites with propagating Ca2+ waves occasionally observed. Firing of Ca2+ transients in ICC-IM is not coordinated with adjacent ICC-IM in a field of view or even with events from other firing sites within a single cell. Ca2+ transients, through activation of Ano1 channels and generation of inward current, cause net depolarization of colonic muscles. Ca2+ transients in ICC-IM rely on Ca2+ release from the endoplasmic reticulum via IP3 receptors, spatial amplification from RyRs and ongoing refilling of ER via the sarcoplasmic/endoplasmic-reticulum-Ca2+ -ATPase. ICC-IM are sustained by voltage-independent Ca2+ influx via store-operated Ca2+ entry. Some of the properties of Ca2+ in ICC-IM in the colon are similar to the behaviour of ICC located in the deep muscular plexus region of the small intestine, suggesting there are functional similarities between these classes of ICC.AbstractA component of the SIP syncytium that regulates smooth muscle excitability in the colon is the intramuscular class of interstitial cells of Cajal (ICC-IM). All classes of ICC (including ICC-IM) express Ca2+ -activated Cl- channels, encoded by Ano1, and rely upon this conductance for physiological functions. Thus, Ca2+ handling in ICC is fundamental to colonic motility. We examined Ca2+ handling mechanisms in ICC-IM of murine proximal colon expressing GCaMP6f in ICC. Several Ca2+ firing sites were detected in each cell. While individual sites displayed rhythmic Ca2+ events, the overall pattern of Ca2+ transients was stochastic. No correlation was found between discrete Ca2+ firing sites in the same cell or in adjacent cells. Ca2+ transients in some cells initiated Ca2+ waves that spread along the cell at ∼100 µm s-1 . Ca2+ transients were caused by release from intracellular stores, but depended strongly on store-operated Ca2+ entry mechanisms. ICC Ca2+ transient firing regulated the resting membrane potential of colonic tissues as a specific Ano1 antagonist hyperpolarized colonic muscles by ∼10 mV. Ca2+ transient firing was independent of membrane potential and not affected by blockade of L- or T-type Ca2+ channels. Mechanisms regulating Ca2+ transients in the proximal colon displayed both similarities to and differences from the intramuscular type of ICC in the small intestine. Similarities and differences in Ca2+ release patterns might determine how ICC respond to neurotransmission in these two regions of the gastrointestinal tract.

Dataset Information

PDGFRα⁺ Interstitial Cells are Effector Cells of PACAP Signaling in Mouse and Human Colon.

Background & aims

Methods

Results

Conclusions

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Dataset Information

PDGFRα+ Interstitial Cells are Effector Cells of PACAP Signaling in Mouse and Human Colon.

Background & aims

Methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

PDGFRα⁺ Interstitial Cells are Effector Cells of PACAP Signaling in Mouse and Human Colon.