Dataset Information

Prolonged inhibition of 5-HT? receptors by palonosetron results from surface receptor inhibition rather than inducing receptor internalization.

ABSTRACT:

Background and purpose

The 5-HT? receptor antagonist palonosetron is an important treatment for emesis and nausea during cancer therapy. Its clinical efficacy may result from its unique binding and clearance characteristics and receptor down-regulation mechanisms. We investigated the mechanisms by which palonosetron exerts its long-term inhibition of 5-HT? receptors for a better understanding of its clinical efficacy.

Experimental approach

Cell surface receptors (recombinantly expressed 5HT?A or 5HT?AB in COS-7 cells) were monitored using [³H]granisetron binding and ELISA after exposure to palonosetron. Receptor endocytosis was investigated using immunofluorescence microscopy.

Key results

Chronic exposure to palonosetron reduced the number of available cell surface [³H]granisetron binding sites. This down-regulation was not sensitive to either low temperature or pharmacological inhibitors of endocytosis (dynasore or nystatin) suggesting that internalization did not play a role. This was corroborated by our observation that there was no change in cell surface 5-HT? receptor levels or increase in endocytic rate. Palonosetron exhibited slow dissociation from the receptor over many hours, with a significant proportion of binding sites being occupied for at least 4 days. Furthermore, our observations suggest that chronic receptor down-regulation involved interactions with an allosteric binding site.

Conclusions and implications

Palonosetron acts as a pseudo-irreversible antagonist causing prolonged inhibition of 5-HT? receptors due to its very slow dissociation. In addition, an irreversible binding mode persists for at least 4 days. Allosteric receptor interactions appear to play a role in this phenomenon.

SUBMITTER: Hothersall JD

PROVIDER: S-EPMC3831706 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Publications

Prolonged inhibition of 5-HT₃ receptors by palonosetron results from surface receptor inhibition rather than inducing receptor internalization.

Hothersall J Daniel JD Moffat Christopher C Connolly Christopher N CN

British journal of pharmacology 20130701 6

<h4>Background and purpose</h4>The 5-HT₃ receptor antagonist palonosetron is an important treatment for emesis and nausea during cancer therapy. Its clinical efficacy may result from its unique binding and clearance characteristics and receptor down-regulation mechanisms. We investigated the mechanisms by which palonosetron exerts its long-term inhibition of 5-HT₃ receptors for a better understanding of its clinical efficacy.<h4>Experimental approach</h4>Cell surface receptors (recombinantly exp ...[more]

PMID: 23581504

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