Table 1.

Neurotransmitters and Neuromodulators That Affect Cholangiocyte Proliferation and Function

Neurotransmitter/neuromodulator	Structure	Receptors	Effect on proliferation/function	References
Met-enkephalin		Delta, mu, and kappa ORs	Increase in opioid synthesis during cholestasis limits excessive cholangiocyte proliferation via delta OR	13
Serotonin 5-hydroxytryptamine		Serotonin 1A and 1B receptors	Autocrine loop based on serotonin secretion that limits the growth of the biliary tree during chronic cholestasis	14
Epinephrine/norepinephrine		β1-ARβ2-AR	Required for cholangiocyte proliferation in response to BDL	15–18
		α1-ARα2-AR	Regulation of secretin-stimulated ductal secretion
Acetylcholine		M3-ACh	Enhances the effect of secretin; required for cholangiocyte proliferation in response to BDL; maintains biliary mass	19–22
GABA		GABAA, GABAB, GABAC receptors	After damage of large bile ducts by GABA, small ducts replenish the biliary tree by amplification of Ca2+-dependent signaling and de novo acquisition of large secretory phenotypes	23
Anandamide		Cb1, VR1	Anandamide inhibits cholangiocyte during BDL via activation of thioredoxin 1/redox factor 1 and AP-1 activation	24
Histamine		H1R, H3R	H3R agonist RAMH inhibits biliary growth of BDL rats; small mouse cholangiocytes proliferate in response to H1R stimulation	25,26

AP-1, activator protein-1; AR, androgen receptor; OR, opiod receptor; RAMH, R-α-methylhistamine dihydrobromide.