Cortistatin Inhibits Intestinal Ion Secretion via Activating the Somatostatin‐2 Receptor in the Submucosal Neurons of the Mouse Colon

Abstract

Background and AimsCortistatin (CST) is a somatostatin‐like neuropeptide that is found in both the central and peripheral nervous system. CST binds with high affinity to all somatostatin receptors and also has actions not shared by somatostatin. We previously found that CST is expressed by enteric neurons in the guinea pig ileum and acts as an inhibitory neurotransmitter in the submucosal plexus. The aim of the present study was to evaluate the effect of CST on neurogenic intestinal secretion.MethodsMucosal/submucosal flat‐sheet preparations from mouse proximal colon were mounted in Ussing flux chambers for measurement of short‐circuit current (Isc) as an indicator of mucosal secretion. Transmural electrical field stimulation (EFS) evoked characteristic biphasic increases in Isc, with an early rapidly rising phase followed by a sustained phase.ResultsApplication of CST‐14, CST‐17, or CST‐29 to the basolateral side of the mucosal/submucosal preparation decreased baseline Isc in a concentration‐dependent manner with an IC50 of 90.5 nM, 52.1 nM, or 102.9 nM, respectively. The somatostatin‐2 receptor (SSTR‐2) antagonist CYN 154806 (1 mM) significantly suppressed CST‐14 (100 nM), CST‐17 (100 nM), or CST‐29 (100 nM)‐evoked ΔIsc by 36.0 ± 8.2% (n=5; P < 0.05), 47.2 ± 11.2% (n=5; P < 0.01), or 51.7.0 ± 8.4% (n=5; P < 0.01), respectively. The neuronal blocker tetrodotoxin (300 nM) significantly reduced CST‐14 (100 nM), CST‐17 (100 nM), or CST‐29 (100 nM)‐evoked ΔIsc by 36.5 ± 2.7% (n=5; P < 0.01), 48.9 ± 11.2% (n=5; P < 0.01), or 49.5 ± 3.6% (n=5; P < 0.01), respectively. All of the CSTs (1 nM – 1 mM) also produced a concentration‐dependent reduction of the EFS‐evoked biphasic secretory responses. The effect of CSTs on the EFS‐evoked responses was antagonized by CYN 154806 (1 mM). Immunohistochemical staining with a CST‐17 polyclonal antibody revealed expression of CST‐17 immunoreactivity (IR) in mouse colonic submucosal neurons. CST‐17‐IR was localized in cholinergic secretomotor neurons but was absent from non‐cholinergic secretomotor neurons and calbindin‐IR neurons.ConclusionsThe results suggest that CST acts at SST‐2 receptors in the submucosal plexus to suppress secretomotor neuronal excitability and neurogenic intestinal secretion in the mouse colon.