Norepinephrine Has Dual Effects on Human Colonic Contractions Through Distinct Subtypes of Alpha 1 Adrenoceptors

Area of Science:

• Gastrointestinal Physiology
• Neurogastroenterology
• Cellular Signaling

Background:

• Colonic smooth muscle function involves a syncytium of smooth muscle cells (SMC), interstitial cells of Cajal (ICC), and platelet-derived growth factor receptor α⁺ (PDGFRα⁺) cells.
• PDGFRα⁺ cells express small conductance Ca²⁺-activated K⁺ (SK) channels, which are activated by enteric neural input to inhibit colonic contractions.
• Previous studies identified α1A adrenoceptors (ARs) in mouse PDGFRα⁺ cells as targets for sympathetic inhibition of colonic motility.

Purpose of the Study:

• To investigate the expression of α1A ARs in human colonic PDGFRα⁺ cells.
• To determine if human PDGFRα⁺ cells, like their mouse counterparts, are targets for sympathetic regulation of colonic motility.

Main Methods:

• Isometric tension recording, intracellular recording, and Ca²⁺ imaging were performed on human colon muscle tissues.
• Responses to α1 AR agonists and electric field stimulation were analyzed in the presence of AR antagonists and neuroleptic reagents.

Main Results:

• Norepinephrine inhibited human colonic contractions via α1A ARs and enhanced them via α1D ARs.
• Inhibitory responses were blocked by apamin, an SK channel antagonist.
• α1 AR agonists increased intracellular Ca²⁺ in PDGFRα⁺ cells, not ICC, and hyperpolarized SMCs, indicating α1 ARs are on PDGFRα⁺ cells.

Conclusions:

• Human colonic contractions are inhibited by α1A ARs located on PDGFRα⁺ cells.
• α1D ARs, located on SMCs, mediate enhanced colonic contractions.
• PDGFRα⁺ cells are crucial targets for sympathetic control of human colonic motility.