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 (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 Ca²⁺ 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 (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 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 Ca²⁺ transients in mouse PIC 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: PIC 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 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.

Keywords: Colon; Inhibitory Effects; Interstitial Cells; Peptidergic Neurotransduction.