Somatostatin subtypes

During incubation in AR42J cells at 37°C, - 1-DOTATATE and Lu-DOTATATE migrate into the cells very rapidly (see Fig. 6.7). Thus, within the first 30 min of incubation, both radioligands practically reach the plateau of the activity associated with internalization (80-85%). Intracellular radioactivity remains at this high level for up to 2 h of incubation. Internalization was shown to be mediated by somatostatin subtype 2 receptors located on the AR42J cell surface, given that the process was inhibited by the presence of IpM TATE. 

The presence of functional somatostatin subtype 2 receptors in dog tumours has been proved. Therefore, the aims here were to study the potential applicability of Tc, in and Y labelled somatostatin analogues in healthy and tumour bearing dogs, and to determine the in vitro stability of the radio-labelled compound after labelhng. 

The curves for three tissues expressing somatostatin subtype 2 receptors are presented in Figs 14.13-14.15. 

The hormone pancreatic polypeptide (PP) is a 36 amino acid peptide, which is closely related to neuropeptide Y and peptide YY PP is mainly found in pancreatic cells distinct from those storing insulin, glucagon or somatostatin. It acts on receptors that belong to the family of neuropeptide Y receptors, particularly on the Y4 subtype. 

Somatostatin. Table 2 Properties of sst subtypes (Data are adapted from [1, 2])... 

The diverse effects of somatostatin, such as inhibition of cell proliferation and hormone release, led to the suggestion that it could be used for the treatment of various diseases. However, its short plasma half-life (less than 3 min) and its relative low receptor subtype... 

Somatostatin-14 Binding to all sst subtypes with high affinity... 

Somatostatin exists in two forms, a 14 and a 28 amino-acid form called SRIF-14 and SRIF-28, respectively. Both are widely distributed in the CNS and the peptide produces inhibitory effects on neurons via G-protein-coupled opening of potassium channels. The original receptor division was twofold with a SRIF-1 and -2 receptor division but it is now clear that what are now known as sst2, 3 and 4 subtypes make up the former receptor while the sstl and 4 receptors are the original SRIF-2 site. 

Law SF, Yasuda K, Bell GI, Reisine T. Gia3 and Goa selectively associate with the cloned somatostatin receptor subtype... 

Liapakis G, Fitzpatrick D, Hoeger C, Rivier ], Vandlen R, Reisine T. Identification of ligand binding determinants in the somatostatin receptor subtypes 1 and 2. J Biol Chern 1996 271 20331-20339. 

Patel, R. C., Lange, D. C. and Patel, Y. C. (2002). Photobleaching fluorescence resonance energy transfer reveals ligand-induced oligomer formation of human somatostatin receptor subtypes. Methods 27, 340-8. 

Although the evolutionary trace method applied to GPCRs (175,185) fails to detect any residues responsible for the subtype-specific heterodimerizafion that has recently been demonstrated for opioid (96), somatostatin (106), and chemokine (98) receptors, correlated mutation analysis had already been demonstrated to be able to identify useful details of molecular specificity (184). Thus, the molecular basis of specificity was hypothesized to reside in outward (i.e., lipid) facing residues of TM5 and TM6 that exhibited evolutionarily correlated mutations and differed between receptor subtypes (184) in the case of dimerization. In the case of oligomers, the key interface between different subtypes was suggested to be the 2,3-interface (152) rather than the 5,6-interface. 

Pfeiffer, M., Koch, T., Schroder, H., et al. (2001) Homo- and heterodimerization of somatostatin receptor subtypes. Inactivation of sst(3) receptor function by heterodimerization with sst(2A). J. Biol. Client. 276,14027-14036. 

Several neurotransmitter and receptor changes are observed in Alzheimer s disease (Nordberg 1992). Losses occur in nicotinic receptors, but muscarinic receptors are relatively preserved. Reductions are also seen in serotonin 5-HTl and 5-HT2 receptors. Glutamate NMDA receptors decrease, while kainate receptors increase. j8-adrenergic and dopamine receptors are preserved. Decreases occur in receptors for somatostatin and neuropeptide Y, but corticotrophin-releasing factor receptors increase. Across all receptor subtypes for which there is a loss, the number of receptors decrease but the affinity constant remains unchanged. 

Roth, A., Kreienkamp, H. J., Meyerhof, W., and Richter, D. (1997) Phosphorylation of four amino acid residues in the carboxyl terminus of the rat somatostatin receptor subtype 3 is crucial for its desensitization and intemahzation. J. Biol. Chem. 272, 23769-23774. 

Rohree, S.P., Biezin, E.T., Mosley, R.T., Berk, S.C., Hutchins, S.M., Shen, D.M., Xiong, Y., Hayes, E.C. Rapid identification of subtype-selective agonists of the somatostatin receptor through combinatorial chemistry. Science 1998, 282, 737-740. 

Other more recent examples of new receptor subt)rpes include neurokinin, melanocortin and somatostatin receptor subt)q)es. Neurokinins (substance P, neurokinin A and neurokinin B) act at three receptor subtypes NK, NK2 and NK3. Selective ligands are being... 

Souers AJ, VirgiUo AA, Rosenquist A, et al. Identification of a potent heterocychc hgand to somatostatin receptor subtype-5 by the synthesis and screening of f -tum mimetic hbraries. / Am Chem Soc 1999 121 1817-25. 

Rohrer SP, Birzin ET, Mosley RT, et al. Rapid identification of subtype-selective agonists of the somatostatin receptor through combinatorial chemistry. Science 1998 282 737- 0. 

Hippocampus CCK, somatostatin, GAD, calcium binding proteins, nicotinic receptors Selective fin density or function of subtypes of GABAergic neurons Positive symptoms (reality distortion)— in left hemisphere... 

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