Biological activity of somatostatin receptors in GC rat tumour somatotrophs:: evidence with sst1-sst5 receptor-selective nonpeptidyl agonists

被引:31
作者
Cervia, D [1 ]
Zizzari, P
Pavan, B
Schuepbach, E
Langenegger, D
Hoyer, D
Biondi, C
Epelbaum, J
Bagnoli, P
机构
[1] Univ Pisa, Dipartimento Fisiol & Biochim G Moruzzi, I-56127 Pisa, Italy
[2] Novartis Pharma AG, Nervous Syst Res, CH-4002 Basel, Switzerland
[3] INSERM, U549, F-75014 Paris, France
[4] Univ Ferrara, Dipartimento Biol, Sez Fis Gen, I-44100 Ferrara, Italy
关键词
SRIF receptor agonists; radioligand binding; intracellular Ca2+; spectral analysis; adenosine; 3; 5 '-cyclic monophosphate; growth hormone; GC cell culture;
D O I
10.1016/S0028-3908(03)00031-5
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The physiological actions of somatostatin-14 (SRIF: somatotrophin release inhibitory factor) receptor subtypes (sst(1)-sst(5)), which are endogenously expressed in growth cells (GC cells), have not yet been elucidated, although there is evidence that sst(2) receptors are negatively coupled to cytosolic free Ca2+ Concentration ([Ca2+](i)) and adenosine 3,5'-cyclic monophosphate (CAMP) accumulation. In addition, both sst(1) and sst(2) receptors are negatively coupled to growth hormone (GH) secretion in GC cells. Here we report on studies concerning the expression, the pharmacology and the functional role of native SRIF receptors in GC cells with the use of five nonpeptidyl agonists, highly selective for each of the SRIF receptors. Radioligand binding studies show that sst(2) and sst(5) receptors are present at different relative densities, while the presence of sst(3) and sst(4) receptors appears to be negligible. The absence of sst(1) receptor binding was unexpected in view of sst(1) receptor functional effects on GH secretion. This suggests very efficient receptor-effector coupling of a low-density population of sst(1) receptors. Functionally, only sst(2) receptors are coupled to the inhibition of [Ca2+](i) and cAMP accumulation and the selective activation of sst(5) receptors facilitates the stimulation of adenylyl cyclase activity through G(i/o) proteins. This effect was not observed when sst(2) and sst(5) receptors were simultaneously activated, suggesting that there is a functional interaction between sst(2) and sst(5) receptors. In addition, sst(1), sst(2) and sst(5) receptor activation inhibits GH release, further indicating that SRIF can modulate GH secretion in GC cells through mechanisms both dependent and independent on [Ca2+](i) and cAMP-dependent pathways. The present data suggest SRIF-mediated functional effects in GC cells to be very diverse and provides compelling arguments to propose that multiple native SRIF receptors expressed in the same cells are not simply redundant, but contribute to marked signalling diversity. (C) 2003 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:672 / 685
页数:14
相关论文
共 61 条
[51]   Characterisation of human recombinant somatostatin receptors. 4. Modulation of phospholipase C activity [J].
Siehler, S ;
Hoyer, D .
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 1999, 360 (05) :522-532
[52]   Characterisation of human recombinant somatostatin receptors. 1. Radioligand binding studies [J].
Siehler, S ;
Seuwen, K ;
Hoyer, D .
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 1999, 360 (05) :488-499
[53]   Somatostatin inhibits glucagon-like peptide-1-induced insulin secretion and proliferation of RINm5F insulinoma cells [J].
Stark, A ;
Mentlein, R .
REGULATORY PEPTIDES, 2002, 108 (2-3) :97-102
[54]   Somatostatin receptor subtypes 2 and 5 inhibit corticotropin-releasing hormone-stimulated adrenocorticotropin secretion from AtT-20 cells [J].
Strowski, MZ ;
Dashkevicz, MP ;
Parmar, RM ;
Wilkinson, H ;
Kohler, M ;
Schaeffer, JM ;
Blake, AD .
NEUROENDOCRINOLOGY, 2002, 75 (06) :339-346
[55]   Somatostatin inhibits insulin and glucagon secretion via two receptor subtypes:: An in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice [J].
Strowski, MZ ;
Parmar, RM ;
Blake, AD ;
Schaeffer, JM .
ENDOCRINOLOGY, 2000, 141 (01) :111-117
[56]   Somatostatin receptor subtypes SSTR2 and SSTR5 couple negatively to an L-type Ca2+ current in the pituitary cell line AtT-20 [J].
Tallent, M ;
Liapakis, G ;
OCarroll, AM ;
Lolait, SJ ;
Dichter, M ;
Reisine, T .
NEUROSCIENCE, 1996, 71 (04) :1073-1081
[57]  
Tomic M, 1999, J NEUROSCI, V19, P7721
[58]   Characterization of a plasma membrane calcium oscillator in rat pituitary somatotrophs [J].
Tomic, M ;
Koshimizu, TA ;
Yuan, D ;
Andric, SA ;
Zivadinovic, D ;
Stojilkovic, SS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (50) :35693-35702
[59]  
Traina G, 1996, J NEUROCHEM, V66, P485
[60]   A calcium-dependent feedback mechanism participates in shaping single NMDA miniature EPSCs [J].
Umemiya, M ;
Chen, NS ;
Raymond, LA ;
Murphy, TH .
JOURNAL OF NEUROSCIENCE, 2001, 21 (01) :1-9