Synergy between 5‐HT₄ receptor stimulation and phosphodiesterase 4 inhibition in facilitating acetylcholine release in human large intestinal circular muscle

Abstract

In human large intestinal circular muscle, the intracellular pathway of 5-HT receptors facilitating cholinergic neurotransmission to large intestinal circular smooth muscle is controlled by PDE4. If the synergy between 5-HT receptor agonism and PDE4 inhibition is confirmed in a functional assay with electrically induced cholinergic contractions of human large intestinal circular smooth muscle strips, combination of a selective 5-HT receptor agonist with a selective PDE4 inhibitor might enhance the in vivo prokinetic effect of the 5-HT receptor agonist in the large intestine.

cAMP Catalyzing Phosphodiesterases Control Cholinergic Muscular Activity But Their Inhibition Does Not Enhance 5-HT4 Receptor-Mediated Facilitation of Cholinergic Contractions in the Murine Gastrointestinal Tract

“…But obviously, in C57Bl/6J murine GI circular muscle, neither cilostamide nor rolipram allows to obtain more pronounced electrically induced cholinergic contractions with prucalopride. This contrasts to the situation in porcine stomach and colon, and human large intestine where the PDE4 inhibitors rolipram and roflumilast enhance the effect of prucalopride on electrically induced cholinergic contractions and/or acetylcholine release ( Priem et al, 2012 , 2013 ; Lefebvre et al, 2016 ; Pauwelyn et al, 2018 ) and points to important species differences. It cannot be excluded that the investigation of other mouse strains might lead to different results.…”

“…It would be optimal to study the influence of PDE inhibition on basal and 5-HT 4 receptor-stimulated acetylcholine release by measuring acetylcholine release directly. But a set of preliminary experiments showed that our method, applied to measure tritiated acetylcholine release in porcine and human GI tissue ( Lefebvre et al, 2016 ; Pauwelyn et al, 2018 ), was not able to pick up consistent values in murine GI tissues. When studying then the influence of PDE inhibitors in a functional model where electrically induced cholinergic muscle contractions are enhanced with a 5-HT 4 receptor agonist, one has to take in account their possible influence at the muscular level.…”

“…The aim of this study was to investigate whether the intraneuronal pathway of 5-HT 4 receptors, enhancing cholinergic neurotransmission towards the circular muscle layer of murine gastric fundus, jejunum, and colon is regulated by PDEs and possibly more particular by PDE4, in view of its role in the signal transduction pathway of facilitating 5-HT 4 receptors in circular muscle of porcine stomach and colon, and human large intestine ( Priem et al, 2012 , 2013 ; Lefebvre et al, 2016 ; Pauwelyn et al, 2018 ). 5-HT 4 receptors signal via cAMP; the classic PDEs 1, 2, and 3 are able to metabolize cAMP as well as cGMP, while PDE4 is cAMP specific ( Maurice et al, 2003 ; Lugnier, 2006 ).…”

“…Selective PDE4 inhibition by rolipram enhanced the facilitation by 5-HT 4 receptor stimulation of electrically induced acetylcholine release and cholinergic contraction in circular muscle strips. We recently showed that PDE4 inhibition with rolipram or roflumilast also enhances the facilitating effect of the 5-HT 4 receptor agonist prucalopride on acetylcholine release in circular muscle strips of human large intestine ( Pauwelyn et al, 2018 ). This suggests the possible usefulness of combining a 5-HT 4 receptor agonist with a PDE4 inhibitor in man, allowing enhanced GI prokinetic effects of the 5-HT 4 receptor agonist in low dose.…”

The Molecular Biology of Phosphodiesterase 4 Enzymes as Pharmacological Targets: An Interplay of Isoforms, Conformational States, and Inhibitors

“…Specifically, PDE4D may mediate this effect upon PDE4 inhibition, as PDE4D has been found to be recruited to CFTR via binding the scaffolding protein Shank2 (Lee et al, 2007). Moreover, PDE4 inhibition can facilitate 5HT4 receptor-mediated acetylcholine release, causing contraction of large intestinal circular smooth muscle (Pauwelyn et al, 2018). Specifically, the PDE4D3 and PDE4D5 isoforms have been found to associate with 5HT4(b) receptors and may, therefore, be involved in gastrointestinal effects caused by PDE4(D) inhibition (Weninger et al, 2014).…”