Modulation of cholecystokinin activity by albumin.

Huang, Shih-Che; Talkad, Venugopal D.; Fortune, Kirk P.; Jonnalagadda, Sreenivasa S.; Severi, Carola; Fave, G. Delle; Gardner, Jerry D.

doi:10.1073/pnas.92.22.10312

Cited by 13 publications

(5 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2B). Addition of serum also reduced CCK-8 uptake in human hepatocytes, which is consistent with cholecystokinin binding to bovine serum albumin (Huang et al, 1995); however, inhibition of CCK-8 uptake was further reduced in the presence of both nilotinib and serum, suggesting that nilotinib-mediated inhibition is likely retained despite protein binding.…”

Section: Resultssupporting

confidence: 64%

Influence of Tyrosine Kinase Inhibition on Organic Anion Transporting Polypeptide 1B3-Mediated Uptake

et al. 2022

View full text Add to dashboard Cite

The organic anion transporting polypeptide family member (OATP) 1B3 is a hepatic uptake transporter that has a broad substrate recognition and plays a significant role in regulating elimination of endogenous biomolecules or xenobiotics. OATP1B3 works in tandem with OATP1B1, with which it shares approximately 80% sequence homology and a high degree of substrate overlap. Despite some substrates being recognized solely by OATP1B3, its ability to compensate for loss of OATP1B1-mediated elimination and recognition by regulatory agencies, little is known about OATP1B3 regulatory factors and how they are involved with drugdrug interaction. It was recently discovered that OATP1B1 function is mediated by the activity of a particular tyrosine kinase that is sensitive to a variety of tyrosine kinase inhibitors (TKIs). This study reports that OATP1B3 is similarly regulated, as at least 50% of its activity is reduced by 20 US Food and Drug Administration -approved TKIs. Nilotinib was assessed as the most potent OATP1B3 inhibitor among the investigated TKIs, which can occur at clinically relevant concentrations and acted predominantly through noncompetitive inhibition without impacting membrane expression. Finally, OATP1B3 function was determined to be sensitive to the knockdown of the Lck/Yes novel tyrosine kinase that is sensitive to nilotinib and has been previously implicated in mediating OATP1B1 activity. Collectively, our findings identify tyrosine kinase activity as a major regulator of OATP1B3 function which is sensitive to kinase inhibition. Given that OATP1B1 is similarly regulated, simultaneous disruption of these transporters can have drastic effects on systemic drug concentrations, which would promote adverse events. SIGNIFICANCE STATEMENTThe organic anion transporting polypeptide family member (OATP) 1B3 is a facilitator of hepatic drug elimination, although much is unknown of how OATP1B3 activity is mediated, or how such regulators contribute to drug-drug interactions. This study reports that OATP1B3 activity is dependent on the Lck/Yes novel tyrosine kinase, which is sensitive to numerous tyrosine kinase inhibitors. These findings provide insight into the occurrence of many clinical drug-drug interactions, and a rationale for future study of tyrosine kinases regulating drug disposition.

show abstract

Section: Resultssupporting

confidence: 64%

Influence of Tyrosine Kinase Inhibition on Organic Anion Transporting Polypeptide 1B3-Mediated Uptake

et al. 2022

View full text Add to dashboard Cite

show abstract

“…A number of studies correlating mutations and/or receptor chimera of CCK A -R and CCK B -R with the binding and biological profiles of ligands have appeared (5)(6)(7)(8)(9)14). However, problems with alteration of receptor function via indirect mechanisms, producing local conformational effects or altering the processing or trafficking of the receptor have been noted (15). Additionally, it is seldom possible to correlate a specific mutation of the receptor with a corresponding interaction site on the peptide [although some exceptions have appeared (6,12)].…”

mentioning

confidence: 99%

Molecular Complex of Cholecystokinin-8 and N-Terminus of the Cholecystokinin A Receptor by NMR Spectroscopy

1999

View full text Add to dashboard Cite

The bimolecular complex of the C-terminal octapeptide of cholecystokinin, CCK-8, with the N-terminus of the CCK(A)-receptor, CCK(A)-R(1-47), has been structurally characterized by high-resolution NMR and computational refinement. The conformation of CCK(A)-R(1-47), within the lipid environment used for the spectroscopic studies, consists of a well-defined alpha-helix (residues 3-9) followed by a beta-sheet stabilized by a disulfide linkage between C18 and C29, leading to the first transmembrane alpha-helix (TM1). Titration of CCK(A)-R(1-47) with CCK-8 specifically affects the NMR signals of W39 of the receptor, in a saturable fashion. This association is specific for CCK-8; no association was observed upon titration of CCK(A)-R(1-47) with other peptide hormones. The ligand/receptor complex was characterized by intermolecular NOEs between Tyr(27) and Met(28) of CCK-8 and W39 of CCK(A)-R(1-47). These findings suggest that CCK-8 binds to CCK(A) with the C-terminus within the seven-helical bundle and the N-terminus of the ligand, projecting out between TM1 and TM7, forming specific interactions with the N-terminus of the CCK(A) receptor. This mode of ligand binding, consistent with published mutagenesis studies, requires variation of the interpretation of recent findings from photoaffinity cross-linking studies.

show abstract

“…However, the main and unique feature of the digestive system mentioned above should be considered as well. To prevent the blood-borne interference (17,19) and reflex actions via neighboring organs (1,10,39) and the CNS (16,26) and to gain better control over the local environment and easier access to gastric receptive fields, an isolated stomachgastric vagus nerve in vitro preparation has been developed (35). In this preparation, the recording site of vagal afferent signals was moved from the cervical vagus to the gastric branch of the ventral subdiaphragmatic vagus nerve trunk (GVA).…”

mentioning

confidence: 99%

“…If the CCK action is indeed mediated by a receptorbinding mechanism, the existing ambient CCK level may affect the CCK sensitivity of GVA terminals. Because the blood-borne interference to the circulating CCK level (17,19) and hence to the CCK level of interstitial fluid is difficult to be controlled in vivo, the appropriate answer to this extrapolation remains unknown.…”

mentioning

confidence: 99%

Effect of CCK pretreatment on the CCK sensitivity of rat polymodal gastric vagal afferent in vitro

Wei

Wang

2000

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

To prevent the blood-borne interference and reflex actions via neighboring organs and the central nervous system, the study was conducted in an in vitro isolated stomach-gastric vagus nerve preparation obtained from overnight-fasted, urethan-anesthetized rats. Afferent unit action potentials were recorded from the gastric branch of the vagus nerve. The left gastric artery was catheterized for intra-arterial injection. In vitro we found that 1) 55/70 gastric vagal afferents (GVAs) were polymodal, responding to CCK-8 and mechanical stimuli, 13 were mechanoreceptive, and 2 were CCK-responsive; 2) sequential or randomized intra-arterial injections of CCK-8 (0.1-200 pmol) dose-dependently increased firing rate and reached the peak rate at 100 pmol; 3) the action was suppressed by CCK-A (Devazepide) but not by CCK-B (L-365,260) receptor antagonist; 4) neither antagonist blocked the mechanosensitivity of GVA fibers. These results are consistent with corresponding in vivo well-documented findings. Histological data indicate that the layered structure of the stomach wall was preserved in vitro for 6-8 h. Based on these results, it seems reasonable to use the in vitro preparation for conducting a study that is usually difficult to be performed in vivo. For instance, because there was no blood supply in vitro, the composition of the interstitial fluid, i.e., the ambient nerve terminals, can be better controlled and influenced by intra-arterial injection of a defined solution. Here we report that acutely changing the ambient CCK level by a conditioning stimulus (a preceding intra-arterial injection of increasing doses of CCK-8) reduced the CCK sensitivity of GVA terminals to a subsequent test stimulus (a constant dose of CCK-8 intra-arterial injection).

show abstract

Modulation of cholecystokinin activity by albumin.

Cited by 13 publications

References 25 publications

Influence of Tyrosine Kinase Inhibition on Organic Anion Transporting Polypeptide 1B3-Mediated Uptake

Influence of Tyrosine Kinase Inhibition on Organic Anion Transporting Polypeptide 1B3-Mediated Uptake

Molecular Complex of Cholecystokinin-8 and N-Terminus of the Cholecystokinin A Receptor by NMR Spectroscopy

Effect of CCK pretreatment on the CCK sensitivity of rat polymodal gastric vagal afferent in vitro

Contact Info

Product

Resources

About