主页 > 医药生命 >
【medical-news】胆囊收缩素对人类胰腺腺泡细胞的
Ashok Salujaa, Craig Logsdonb, Pramod Gargc
published online 10 July 2008.
Refers to article:
Direct Activation of Cytosolic Ca2+ Signaling and Enzyme Secretion by Cholecystokinin in Human Pancreatic Acinar Cells , 08 May 2008
John A. Murphy, David N. Criddle, Mark Sherwood, Michael Chvanov, Rajarshi Mukherjee, Euan McLaughlin, David Booth, Julia V. Gerasimenko, Michael G.T. Raraty, Paula Ghaneh, John P. Neoptolemos, Oleg V. Gerasimenko, Alexei V. Tepikin, Gary M. Green, Joseph R. Reeve, Ole H. Petersen, Robert Sutton
Gastroenterology
August 2008 (Vol. 135, Issue 2, Pages 632-641)
Abstract | Full Text | Full-Text PDF (2048 K
Article Outline
• References
• Copyright
See “Direct activation of cytosolic Ca2+ signaling and enzyme secretion by cholecystokinin in human pancreatic acinar cells,” by Murphy JA, Criddle DN, Sherwood M, et al, on page 632.
During 350 billion years of life on Earth, humans and rodents (rats and mice) diverged from each other about 30–40 million years before humans and chimps did, but later than humans and dogs, according to estimates based on the homology of orthologus genes.1 Although humans and rodents have many similarities, whether important differences exist between them in regard to the regulation of pancreatic secretion by the gastrointestinal hormone cholecystokinin (CCK) has been a controversial subject that is being raised anew in the current paper by Murphy et al.2
CCK is a prototypical brain–gut peptide that has hemacrine and autocrine actions in the gut and acts as a neurotransmitter in the brain. The gene for CCK is highly conserved across different species, with 71% homology between human and mouse CCK genes.3 At physiologic levels, CCK acts primarily via CCK-A receptors where it has a 1,000-fold higher affinity than gastrin, a closely related gastrointestinal hormone. Gastrin, by contrast, acts primarily through CCK-B receptors because of its lower affinity for the CCK-A receptor. Plasma levels of CCK in humans range from a pre-meal low of ∼1 pmol/L to a postprandial high of <10 pmol/L; gastrin circulates at much higher levels, from 10 to 20 pmol/L basal to >100 pmol/L after a meal.4 Such a difference in circulating levels explains their respective actions on specific receptors in the physiologic state.
CCK stimulates pancreatic secretion in both humans and rodents. Therefore, it was natural to believe that the actions of CCK in the pancreas should be similar in humans and rodents, and should involve the CCK-A receptor. Initially, CCK was thought to mediate pancreatic acinar cell secretion entirely by direct interaction with CCK-A receptors on acinar cells. However, convincing studies in humans and rodents indicated that cholinergic vagal innervation is an important pathway for CCK mediated stimulation of pancreatic secretion in both humans and rodents.5 The mechanism responsible for this action was found to involve afferent vagal cholinergic fibers bearing CCK-A receptors. CCK binds to these receptors on vagal neurons and influences the pancreatic secretion via the cholinergic postganglionic vagal efferent fibers on the pancreatic acini with acetylcholine (ACh) being the final neurotransmitter acting on the muscarinic receptors (m3 AChR).6 Thus, it seemed likely that CCK acted through CCK-A receptors, both directly on acinar cells as well as through the neural pathways to cause pancreatic secretion.
This happy compromise, that both direct and indirect actions of CCK are responsible for pancreatic secretion, was brought into question when the distribution of CCK receptors was analyzed. High levels of CCK-A, but not CCK-B, receptors were demonstrated clearly on rodent pancreatic acinar cells.7 That CCK can act on these CCK-A receptors and stimulate the secretion of digestive enzymes was confirmed by multiple observations, which included CCK-A receptor mRNA expression and receptor-ligand binding on the acinar cells, functional responses of acinar cells to picomolar concentrations of CCK in the form of intracellular Ca++ signaling and secretion of digestive enzymes, as well as in vivo increase in pancreatic secretion by CCK that was inhibited by CCK-A antagonists but not atropine.8, 9 So, for rodents it is established that both direct and indirect regulation of pancreatic secretion by CCK exists.
Whether the same can be said for humans is not as clear. There are 3 critical issues to be addressed in the debate upon whether or not human acinar cells respond directly to CCK. First, which CCK receptors, if any, are expressed on human pancreatic acinar cells; second, do they respond to endogenous CCK directly? Third, what are the relative contributions of vagal and direct CCK stimulation to secretory responses of acinar cells in vivo? The first issue, that is, the presence of CCK receptors on acinar cells, has been controversial. CCK receptor mRNA levels are reduced greatly in human pancreas compared with rodents and, importantly, the CCK-B receptor predominates in the human pancreas.7, 10 Ji et al10 reported the near absence of CCK-A receptor mRNA in human acinar cells whereas CCK-B receptor mRNA was present at very low levels. Immunohistochemical studies have also failed to localize CCK-A receptors to the human pancreas. Nishimori et al,11 however, found that CCK-A receptor mRNA was expressed in the human pancreas to approximately 394 copies per cell, although CCK-A mRNA was absent by Northern blotting. More important, they demonstrated expression of CCK-A receptors in human fetal, infant, and adult pancreatic acinar cells. A more recent study by Galindo et al,12 using advanced techniques of quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and QZyme oligonucleotide, found higher levels of CCK-A receptor mRNA in human acinar cells. They used multiple sets of primers (qRT-PCR) for various size fragments of the CCK receptor gene. Furthermore, not all types of the primer sets were equally efficient. The authors found that GGA- and GAA-rich nucleotide sequences resulted in polymerase slippage, probably owing to the generation of hairpin loops within the sequence, a likely reason for inefficiency of polymerases. Taken together, the data suggest that CCK-A receptor levels are likely to be present on the human acinar cells, although at much lower levels than CCK-B receptors.
阅读本文的人还阅读：
作者:admin@医学,生命科学 2011-01-18 17:14
医学,生命科学网