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Editorial

Mounting evidence against the role of ICC in neurotransmission to smooth muscle in the gut

¹VA Medical Center ²HARVARD MEDICAL SCHOOL

Submitted 16 October 2009 ; revision received 29 October 2009 ; accepted in final form 29 October 2009

ABSTRACT

How nerves transmit their signals to regulate activity of smooth muscle is of fundamental importance to autonomic and enteric physiology, clinical medicine and therapeutics. A traditional view of neurotransmission to smooth muscles has been that motor nerve varicosities release neurotransmitters that act on receptors on smooth muscles to cause their contraction or relaxation via electromechanical and phamacomechanical signaling pathways in the smooth muscle. In recent years, an old hypothesis that certain interstitial cells of Cajal (ICC) may transduce neural signals to smooth muscle cells has been resurrected. This later hypothesis is based on indirect evidence of closer proximity and presence of synapses between the nerve varicosities and ICC, gap junctions between ICC and smooth muscles and presence of receptors and signaling pathways for the neurotransmitters and ICC. This indirect evidence is at best circumstantial. The direct evidence is based on the reports of loss of neurotransmission in mutant animals lacking ICC due to c-kit receptor deficiency. However, a critical analysis of the recent data show that animals lacking ICC have normal cholinergic and purinergic neurotransmission and tachykinergic neurotransmission is actually increased. The status of nitrergic neurotransmission in in c-kit deficient animals has been controversial. However, reports suggest that 1) nitrergic neurotransmission in the internal anal sphincter does not require ICC. 2) in vivo phenotype of ICC deficiency does not resemble nNOS deficiency. 3) Most recent report in this issue of the Journal concludes that impaired nitrergic neurotransmission may be due to smooth muscle defects associated with c-kit receptor deficiency.

intestinal phenotype of WS/WS; nitrergic neurotransmission; gastroparesis; bile gastritis