TY - JOUR
T1 - Metabotropic Signal Transduction for Bradykinin in Submucosal Neurons of Guinea Pig Small Intestine
AU - Hu, Hong Zhen
AU - Gao, Na
AU - Liu, Sumei
AU - Ren, Jun
AU - Xia, Yun
AU - Wood, Jackie D.
PY - 2004/4
Y1 - 2004/4
N2 - Intracellular recording methods with "sharp" microelectrodes were used to study signal transduction mechanisms underlying the excitatory action of bradykinin (BK) in morphologically identified neurons in the small intestinal submucosal plexus. Exposure to BK evoked slowly activating membrane depolarization and enhanced excitability associated with increased input resistance in AH-type and decreased input resistance in S-type neurons. Preincubation with pertussis toxin did not affect the BK-evoked responses. Pretreatment with the cyclooxygenase inhibitors indomethacin or piroxicam suppressed or abolished the BK-evoked responses. Application of prostaglandin (PG) E2 or PG analogs evoked BK-like depolarizing responses in the submucosal plexus with a potency order of PGE2 > PGE1 > 17-phenyl trinor-PGE2 > PGI2 > sulprostone > PGF2α. Depolarizing responses to bradykinin or PGE 2 in S-type neurons were suppressed in the presence of the phospholipase C inhibitor U73122 [(1-6-[([17β ]-3-methoxyestra-1,3,5[10]-tren-17-71)amino]hexyl)-1H-pyrrole-2,5-dione)], but not the inactive analog U73343 [(1-6-[([17β ]-3-methoxyestra-1,3,5[10]trien-17yl)amino]hexyl)-2,5-pyrrolidinedione)]. The inositol-1,4,5-trisphosphate receptor antagonist 2-aminoethoxydiphenylborane and the calmodulin inhibitor W-7, but not ryanodine, suppressed both bradykinin- and PGE2-evoked responses. KN-62, an inhibitor of calmodulin kinases, or GF109203X, a specific protein kinase C inhibitor, suppressed both BK- and PGE2-evoked depolarizing responses. Selective protein kinase A inhibitors did not alter BK- or PGE2-evoked depolarizing responses in S neurons. The results suggest that BK stimulates synthesis and release of PGE2, which acts at EP1 receptors to evoke depolarizing responses in submucosal neurons. The postreceptor transduction cascade includes activation of phospholipase C, inositol-1,4,5-trisphosphate production, intraneuronal Ca2+ mobilization, activation of protein kinase C and/or calmodulin kinases, and phosphorylation of cationic channels.
AB - Intracellular recording methods with "sharp" microelectrodes were used to study signal transduction mechanisms underlying the excitatory action of bradykinin (BK) in morphologically identified neurons in the small intestinal submucosal plexus. Exposure to BK evoked slowly activating membrane depolarization and enhanced excitability associated with increased input resistance in AH-type and decreased input resistance in S-type neurons. Preincubation with pertussis toxin did not affect the BK-evoked responses. Pretreatment with the cyclooxygenase inhibitors indomethacin or piroxicam suppressed or abolished the BK-evoked responses. Application of prostaglandin (PG) E2 or PG analogs evoked BK-like depolarizing responses in the submucosal plexus with a potency order of PGE2 > PGE1 > 17-phenyl trinor-PGE2 > PGI2 > sulprostone > PGF2α. Depolarizing responses to bradykinin or PGE 2 in S-type neurons were suppressed in the presence of the phospholipase C inhibitor U73122 [(1-6-[([17β ]-3-methoxyestra-1,3,5[10]-tren-17-71)amino]hexyl)-1H-pyrrole-2,5-dione)], but not the inactive analog U73343 [(1-6-[([17β ]-3-methoxyestra-1,3,5[10]trien-17yl)amino]hexyl)-2,5-pyrrolidinedione)]. The inositol-1,4,5-trisphosphate receptor antagonist 2-aminoethoxydiphenylborane and the calmodulin inhibitor W-7, but not ryanodine, suppressed both bradykinin- and PGE2-evoked responses. KN-62, an inhibitor of calmodulin kinases, or GF109203X, a specific protein kinase C inhibitor, suppressed both BK- and PGE2-evoked depolarizing responses. Selective protein kinase A inhibitors did not alter BK- or PGE2-evoked depolarizing responses in S neurons. The results suggest that BK stimulates synthesis and release of PGE2, which acts at EP1 receptors to evoke depolarizing responses in submucosal neurons. The postreceptor transduction cascade includes activation of phospholipase C, inositol-1,4,5-trisphosphate production, intraneuronal Ca2+ mobilization, activation of protein kinase C and/or calmodulin kinases, and phosphorylation of cationic channels.
UR - http://www.scopus.com/inward/record.url?scp=1642336853&partnerID=8YFLogxK
U2 - 10.1124/jpet.103.059204
DO - 10.1124/jpet.103.059204
M3 - Article
C2 - 14718601
AN - SCOPUS:1642336853
SN - 0022-3565
VL - 309
SP - 310
EP - 319
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -