Disease relevance of NMBR

• Additionally, we have detected transcripts for GRPR and NMBR in four of seven and seven of seven cases, respectively, of cultured non-small cell lung carcinomas (NSCLC) [1].
• Our study indicates that GRPR and NMBR are widely distributed in human ovarian carcinomas with BRS-3 being found in Stage IV tumors [2].
• Both GRP-R and NMB-R mRNA expression was detected at varying levels in a panel of human lung cancer cell lines [3].
• The mechanism is not known, and a potent and specific GRP-R antagonist BIM26226, which has low affinity for NMB-R, was used in vivo in athymic nude mice bearing gastrinoma subcutaneously [4].

High impact information on NMBR

• Existence of NMB-R has been demonstrated in several brain regions, notably in olfactory and thalamic regions, and in gastrointestinal tracts [5].
• We detected low level expression of the gastrin-releasing peptide and neuromedin-B receptor mRNAs in cultures of human bronchial epithelium from 4 of 6 individuals [6].
• Potential candidate genes include ESR1, OPRM1, and NMBR [7].
• Four amino acid residues are critical for high affinity binding of neuromedin B to the neuromedin B receptor [8].
• In contrast, these four amino acid substitutions in BRS-3 did not result in the formation of a high affinity binding site for the recently described non-peptide NMB-R antagonist PD168368 [8].

Biological context of NMBR

• Results of 125I-[D-Tyr0]NMB displacement assays using unlabeled NMB for competition indicated that high affinity NMB binding was determined by amino acid sequences in transmembrane domain V (TM-V) of the NMB-R [9].
• As a first step, we examined the distribution of expression of GRP-R and NMB-R mRNA during rat embryonic development to identify changing spatio-temporal patterns of gene expression [10].
• Comparison of the mouse and human receptor sequences indicates 90% (NMB-R) and 85% (BRS-3) sequence homology at the amino-acid level [11].

Anatomical context of NMBR

• Using the reverse transcription-polymerase chain reaction (RT-PCR), we have detected mRNA for the neuromedin B receptor (NMBR) in all 14 of the NSCLC cell lines examined [12].
• All actions of bombesin were blocked by BME (D-Phe(6)-bombesin-(6-13)-methylester), a selective GRP receptor antagonist, but not by the NMB receptor antagonist BIM-23127 (D-Nal-cyclo[Cys-Tyr-D-Trp-Orn-Val-Cys]-Nal-NH(2)).We conclude that HPAF cells express mRNA for GRP receptors and that functional receptors are present in the cell membrane [13].
• Only NMB-R-null mice accumulated fewer lung mast cells after bombesin treatment [14].
• After expression in Xenopus oocytes, a GRP-R-specific antagonist was effective in blocking responses elicited from the cloned GRP-R, but not the NMB-R [3].
• In contrast, the distribution of expression of NMB-R mRNA is more limited (upper gastrointestinal tract, bladder, and central nervous system) and is observed at later embryonic stages [10].

Associations of NMBR with chemical compounds

• The fifth transmembrane segment of the neuromedin B receptor is critical for high affinity neuromedin B binding [9].
• Using clones stably transfected with the NMB receptor however, we found that NMB stimulated the incorporation of [3H]thymidine 2.5- to 8-fold over basal levels [15].
• The data suggest that ICI 216140 and DPDM-bombesin ethylamide behave as agonists at the neuromedin B receptor, perhaps as a consequence of neuromedin B receptor overexpression [16].

Other interactions of NMBR

• We have also amplified message for NMBR in five of five fresh bronchial biopsies, but message for GRPR could not be detected [1].
• An amplified fragment was detected for GRPR in seven of nine cases, for NMBR in six of 10 cases, and the BRS-3 in three of nine cases [1].
• The neuromedin B receptor antagonist, BIM-23127, is a potent antagonist at human and rat urotensin-II receptors [17].
• In conclusion, BIM- 23127 is the first hUT receptor antagonist identified to date and should not be considered as a selective neuromedin B receptor antagonist [17].

Analytical, diagnostic and therapeutic context of NMBR

• Recent analysis using NMB-R-deficient mice, generated by gene-targeting technique, enables to distinguish functional properties of NMB-R from GRP-R [5].
• PD 168368 should prove useful for delineating the biological role of NMB and selectively blocking NMB signaling in bioassays and as a lead for the development of more selective nonpeptide antagonists for the NMB receptor [18].
• CONCLUSION: 177Lu-AMBA binds with nanomolar affinity to GRP-R and NMB-R, has low retention of radioactivity in kidney, demonstrates a very favorable risk-benefit profile, and is in phase I clinical trials [19].
• By receptor autoradiography, Lu-AMBA binds specifically to GRP-R (0.8 nmol/L) and to the neuromedin B receptor (NMB-R) (0.9 nmol/L), with no affinity for the bb3 receptor (>1,000 nmol/L) [19].
• By immunohistochemistry, both NMB and NMB-R were expressed in normal and cancerous colonic epithelial tissues [20].

References