Abstract
Cholecystokinin (CCK) directly activates vagal afferent neurons resulting in coordinated
gastrointestinal functions and satiation. In vitro, the effects of CCK on dissociated vagal afferent neurons are mediated via activation
of the vanilloid family of transient receptor potential (TRPV) cation channels leading
to membrane depolarization and an increase in cytosolic calcium. However, the cellular
transduction pathway(s) involved in this process between CCK receptors and channel
opening have not been identified. To address this question, we monitored CCK-induced
cytosolic calcium responses in dissociated nodose neurons from rat in the presence
or absence of reagents that interact with various intracellular signaling pathways.
We found that the phospholipase C (PLC) inhibitor U-73122 significantly attenuated
CCK-induced responses, whereas the inactive analog U-73433 had no effect. Responses
to CCK were also cross-desensitized by a brief pretreatment with m-3M3FBS, a PLC stimulator.
Together these observations strongly support the participation of PLC in the effects
of CCK on vagal afferent neurons. In contrast, pharmacological antagonism of phospholipase
A2, protein kinase A, and phosphatidylinositol 3-kinase revealed that they are not critical
in the CCK-induced calcium response in nodose neurons. Further investigations of the
cellular pathways downstream of PLC showed that neither protein kinase C (PKC) nor
generation of diacylglycerol (DAG) or release of calcium from intracellular stores
participates in the response to CCK. These results suggest that alteration of membrane
phosphatidylinositol 4,5-bisphosphate (PIP2) content by PLC activity mediates CCK-induced calcium response and that this pathway
may underlie the vagally-mediated actions of CCK to induce satiation and alter gastrointestinal
functions.
Keywords
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Article info
Publication history
Published online: June 10, 2011
Accepted:
May 19,
2011
Received in revised form:
May 18,
2011
Received:
December 28,
2010
Identification
Copyright
© 2011 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
