Although the source of embryonic stem (ES) cells presents ethical concerns, their use may lead to many clinical benefits if differentiated cell types can be derived from them and used to assemble functional organs. In pancreas, insulin is produced and secreted by specialized structures, islets of Langerhans. Diabetes, which affects 16 million people in the United States, results from abnormal function of pancreatic islets. We have generated cells expressing insulin and other pancreatic endocrine hormones from mouse ES cells. The cells self-assemble to form three-dimensional clusters similar in topology to normal pancreatic islets where pancreatic cell types are in close association with neurons. Glucose triggers insulin release from these cell clusters by mechanisms similar to those employed in vivo. When injected into diabetic mice, the insulin-producing cells undergo rapid vascularization and maintain a clustered, islet-like organization.
Abstract:We report here the molecular cloning of three tissues, including rodent and human brain (Eglen et new splice variants of the human serotonin 5-hydroxyal., 1995), rodent, pig, dog, and human gastrointestinal tryptamine4 (h5-HT4) receptor, which we named h5-tract, and human and pig heart (Hegde and Eglen, HT4(b), h5-HT4(~), and h5-HT4(d). The sequence following 1996). In the mammalian brain, 5-HT4 receptors conthe splicing site at Leu355 in the C-terminal tail of h5HT4 (b) tribute to the control of dopamine secretion (Bondisplays a 74% protein identity with the same region in homme et al., 1995) and regulate learning and longthe long form of the rat 5-HT4 receptor (r5-HT4L) but is shorter by 18 amino acids compared to its rat counterterm memory through modulation of acetylcholine repart. The splice variants h5-HT4(~)and h5-HT4(d) are the lease (Marchetti-Gauthier et al., 1997). In peripheral first of their kind to be described, in any animal species, tissues, 5-HT4 receptors have been shown to regulate The C terminus of h5-HT4(C) displays a high number of gastrointestinal tract motility, intestinal electrolyte seputative phosphorylation sites. The h5-HT4(d) isoform corcretion, adrenal corticosteroid secretion, bladder conresponds to an ultrashort form of the receptor, with a traction, and atrial contractility (for review, see Hegde truncation two amino acids after the splicing site. Tissue and Eglen, 1996). distribution studies revealed some degree of specificity 5-HT4 receptors are thought to be involved in vanin the pattern of expression of the different isoforms ous central and peripheral disorders, including cardiac within the human body. The four splice variants tranarrhythmias (Kaumann, 1994) and neurodegenerative siently expressed in COS-7 cells displayed an identical 5-HT4 pharmacological profile and showed a similar abildiseases (Reynolds et al., 1995; Wong et al., 1996). ity to stimulate adenylyl cyclase activity in the presence Moreover, the development of 5-HT4 receptor agonists of 5-HT. The stimulatory pattern of cyclic AMP formation in response to the 5-HT4 agonist renzapride was found _______________________________________________ to be significantly different between h5~HT41a1and the Received September 1, 1997; revised manuscript received Noother h5-HT4 isoforms, indicating that the splice variants vember 27, 1997; accepted December 22, 1997. may differ in the way they trigger the signal transduction
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