TY - JOUR
T1 - Thrombin and mast cell tryptase regulate guinea-pig myenteric neurons through proteinase-activated receptors-1 and -2
AU - Corvera, Carlos U.
AU - Déry, Olivier
AU - McConalogue, Karen
AU - Gamp, Patrick
AU - Thoma, Mark
AU - Al-Ani, Bahjat
AU - Caughey, George H.
AU - Hollenberg, Morley D.
AU - Bunnett, Nigel W.
PY - 1999/6/15
Y1 - 1999/6/15
N2 - 1. Proteases regulate cells by cleaving proteinase-activated receptors (PARs). Thrombin and trypsin cleave PAR-1 and PAR-2 on neurons and astrocytes of the brain to regulate morphology, growth and survival. We hypothesized that thrombin and mast cell tryptase, which are generated and released during trauma and inflammation, regulate enteric neurons by cleaving PAR-1 and PAR-2. 2. We detected immunoreactive PAR-1 and PAR-2 in > 60% of neurons from the myenteric plexus of guinea-pig small intestine in primary culture. A large proportion of neurons that expressed substance P, vasoactive intestinal peptide or nitric oxide synthase also expressed PAR-1 and PAR-2. We confirmed expression of PAR-1 and PAR-2 in the myenteric plexus by RT-PCR using primers based on sequences of cloned guinea-pig receptors. 3. Thrombin, trypsin, tryptase, a filtrate from degranulated mast cells, and peptides corresponding to the tethered ligand domains of PAR-1 and PAR-2 increased [Ca2+](i) in > 50% of cultured myenteric neurons. Approximately 60% of neurons that responded to PAR-1 agonists responded to PAR-2 agonists, and > 90% of PAR-1 and PAR-2 responsive neurons responded to ATP. 4. These results indicate that a large proportion of myenteric neurons that express excitatory and inhibitory neurotransmitters and purinoceptors also express PAR-1 and PAR-2. Thrombin and tryptase may excite myenteric neurons during trauma and inflammation when prothrombin is activated and mast cells degranulate. This novel action of serine proteases probably contributes to abnormal neurotransmission and motility in the inflamed intestine.
AB - 1. Proteases regulate cells by cleaving proteinase-activated receptors (PARs). Thrombin and trypsin cleave PAR-1 and PAR-2 on neurons and astrocytes of the brain to regulate morphology, growth and survival. We hypothesized that thrombin and mast cell tryptase, which are generated and released during trauma and inflammation, regulate enteric neurons by cleaving PAR-1 and PAR-2. 2. We detected immunoreactive PAR-1 and PAR-2 in > 60% of neurons from the myenteric plexus of guinea-pig small intestine in primary culture. A large proportion of neurons that expressed substance P, vasoactive intestinal peptide or nitric oxide synthase also expressed PAR-1 and PAR-2. We confirmed expression of PAR-1 and PAR-2 in the myenteric plexus by RT-PCR using primers based on sequences of cloned guinea-pig receptors. 3. Thrombin, trypsin, tryptase, a filtrate from degranulated mast cells, and peptides corresponding to the tethered ligand domains of PAR-1 and PAR-2 increased [Ca2+](i) in > 50% of cultured myenteric neurons. Approximately 60% of neurons that responded to PAR-1 agonists responded to PAR-2 agonists, and > 90% of PAR-1 and PAR-2 responsive neurons responded to ATP. 4. These results indicate that a large proportion of myenteric neurons that express excitatory and inhibitory neurotransmitters and purinoceptors also express PAR-1 and PAR-2. Thrombin and tryptase may excite myenteric neurons during trauma and inflammation when prothrombin is activated and mast cells degranulate. This novel action of serine proteases probably contributes to abnormal neurotransmission and motility in the inflamed intestine.
UR - http://www.scopus.com/inward/record.url?scp=0345004978&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0345004978&partnerID=8YFLogxK
U2 - 10.1111/j.1469-7793.1999.0741s.x
DO - 10.1111/j.1469-7793.1999.0741s.x
M3 - Article
C2 - 10358115
AN - SCOPUS:0345004978
SN - 0022-3751
VL - 517
SP - 741
EP - 756
JO - Journal of Physiology
JF - Journal of Physiology
IS - 3
ER -