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Adhesion G protein–coupled receptors (AGPCRs) are a thirty-three-member subfamily of Class B GPCRs that control a wide array of physiological processes and are implicated in disease. AGPCRs uniquely contain large, self-proteolyzing extracellular regions that range from hundreds to thousands of residues in length. AGPCR autoproteolysis occurs within the extracellular GPCR autoproteolysis-inducing (GAIN) domain that is proximal to the N terminus of the G protein–coupling seven-transmembrane–spanning bundle. GAIN domain–mediated self-cleavage is constitutive and produces two-fragment holoreceptors that remain bound at the cell surface. It has been of recent interest to understand how AGPCRs are activated in relation to their two-fragment topologies. Dissociation of the AGPCR fragments stimulates G protein signaling through the action of the tethered-peptide agonist stalk that is occluded within the GAIN domain in the holoreceptor form. AGPCRs can also signal independently of fragment dissociation, and a few receptors possess GAIN domains incapable of self-proteolysis. This has resulted in complex theories as to how these receptors are activated in vivo, complicating pharmacological advances. Currently, there is no existing structure of an activated AGPCR to support any of the theories. Further confounding AGPCR research is that many of the receptors remain orphans and lack identified activating ligands. In this review, we provide a detailed layout of the current theorized modes of AGPCR activation with discussion of potential parallels to mechanisms used by other GPCR classes. We provide a classification means for the ligands that have been identified and discuss how these ligands may activate AGPCRs in physiological contexts.

The residue lysine 28 (K28) is known to form an important salt bridge that stabilizes the Aβ amyloid structure, and acetylation of lysine 28 (K28Ac) slows the Aβ42 fibrillization rate but does not affect fibril morphology. On the other hand, acetylation of lysine 16 (K16Ac) residue greatly diminishes the fibrillization property of Aβ42 peptide and also affects its toxicity. This is due to the fact that lysine 16 acetylated amyloid beta peptide forms amorphous aggregates instead of amyloid fibrils. This is likely a result of increased hydrophobicity of the K16-A21 region due to K16 acetylation, as confirmed by molecular dynamic simulation studies. The calculated results show that the hydrophobic patches of aggregates from acetylated peptides were different when compared to wild-type (WT) peptide. K16Ac and double acetylated (KKAc) peptide aggregates show significantly higher cytotoxicity compared to the WT or K28Ac peptide aggregates alone. However, the heterogeneous mixture of WT and acetylated Aβ42 peptide aggregates exhibited higher free radical formation as well as cytotoxicity, suggesting dynamic interactions between different species could be a critical contributor to Aβ pathology.

Sterically hindered fluorescent probes (A-C) have been developed by introducing 2-aminophenylboronic acid pinacol ester to a traditional, A, a near-infrared rhodamine dye, B, and a near-infrared hemicyanine dye, C, forming closed spirolactam ring structures. Probe A was non-fluorescent under basic pH conditions whereas probes B and C were moderately fluorescent with fluorescence quantum yields of 9% and 5% in pH 7.4 PBS buffer containing 1% ethanol, respectively. With all probes increasing acidity leads to significant increases in fluorescence at 580 nm, 644 and 744 nm for probes A, B and C with fluorescence quantum yields of 26%, 21% and 10% in pH 4.5 PBS buffer containing 1% ethanol, respectively. Probes A, B and C were calculated to have pKa values of 5.81, 5.45 and 6.97. The difference in fluorescence under basic conditions is ascribed to easier opening of the closed spirolactam ring configurations due to significant steric hindrance between the 2-aminophenylboronic acid pinacol ester residue and an adjacent H atom in the xanthene derivative moiety in probe B or C. The probes show fast, reversible, selective and sensitive fluorescence responses to pH changes, and are capable of sensing lysosomal pH variations in living cells.

We report two new near-infrared fluorescent probes based on Rhodol counterpart fluorophore platforms functionalized with dipicolylamine Zn(II)-binding groups. The combinations of the pendant amines and fluorophores provide the probes with an effective three-nitrogen-atom and one-oxygen-atom binding motif. The fluorescent probes with large Stokes shifts offer sensitive and selective florescent responses to Zn(II) ions over other metal ions, allowing a reversible monitoring of Zn(II) concentration changes in living cells, and detecting intracellular Zn(II) ions released from intracellular metalloproteins.

We report five fluorescent probes based on coumarin-hybridized fluorescent dyes with spirolactam ring structures (A–E) to detect pH changes in live cells by monitoring visible and near-infrared fluorescence changes. Under physiological or basic conditions, the fluorescent probes A, B, C, D, and E preserve their spirolactam ring-closed forms and only display fluorescent peaks in the visible region corresponding to coumarin moieties at 497, 483, 498, 497 and 482 nm, respectively. However, at acidic pH, the rings of the spirolactam forms of the fluorescent probes A, B, C, D, and E open up, generating new near-infrared fluorescence peaks at 711, 696, 707, 715, and 697 nm, respectively, through significantly extended π-conjugation to coumarin moieties of the fluorophores. The fluorescent probes B and E can be applied to visualize pH changes by monitoring visible as well as near-infrared fluorescence changes. This helps avoid fluorescence imaging blind spots at neutral or basic pH, which typical pH fluorescent probes encounter. The probes exhibit high sensitivity to pH changes, excellent photostability, low auto-fluorescence background and good cell membrane permeability.

Background: Avipattikar churna, a poly-herbal formulation, is one of the popular ayurvedic formulations which is used for peptic ulcer diseases but the scientific documentation with regards to its effect for the indication is lacking. Aims: This study was carried out to evaluate the anti-secretory and the anti-ulcerogenic activities of the churna and to compare its activity with that of ranitidine in a pyloric ligated model of rats. Material and methods: Four groups of rats with 6 animals in each served as the ulcer controls, churna low dose (500 mg/kg), churna high dose (750mg/kg) and ranitidine (25mg/kg). The control group rats received only vehicle (2% (v/v) gum acacia), while the rats of the other groups received the respective dose of the churna or ranitidine which was suspended in the vehicle. The treatments were given twice a day, orally, for two days. After 1 hour of the last dose, pyloric ligations were performed and the rats were sacrificed for evaluation after four hours of the ligations. The gastric contents were collected and its volume, pH and acidity were measured. The numbers of ulcers and their lengths were measured which were used to calculate the gastric irritancy index and the curative ratio. The histological examinations of the gastric tissues were also performed. Results: The churna, in both doses, significantly decreased the volumes of the gastric contents, the ulcer score, the length of the ulcer, the gastric irritancy index and pH increased as compared to those in the control group. The effects of the churna were comparable to that of ranitidine. The histopathological evaluation of the gastric tissue also supported the results. Conclusion: Avipattikar churna has anti-secretory and anti-ulcerogenic effects which are comparable to those of ranitidine in peptic ulcer diseases.