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From receptor internalization to nuclear translocation. New targets for long-term pharmacology
1School of Pharmacy, University of Louvain, Brussels, Belgium.
Abstract:
Receptors involved in intercellular communication at the cell surface share the capacity to desensitize through molecular and cellular mechanisms. Cellular desensitization is a rapid and dynamic process whereby membrane receptors internalize in response to an excess of agonists. The internalized receptors may recycle rapidly or undergo down-regulation when following a degradative pathway. However, receptor internalization does not necessarily mean degradation; it also represents the initial step of a retrograde signalling system whereby an "interiorized" message, the ligand-receptor complex, can be transported in contrast to second messengers, along axons or in the cytoplasm leading to long-term effects in the nucleus. Such "third messengers" have to undergo nuclear translocation to serve as transcriptional regulators in the control of gene expression. The "third messengers" are thus cytoplasmic proteins, including the receptor itself, which may be associated with internalized vesicles and released by mechanisms which have not yet been elucidated. They represent already good targets for the development of new drugs, and multi-targeting and synergistic approaches are likely to increase their usefulness.
Insights
Cell surface receptors desensitize by internalizing, a process that can lead to retrograde signaling. This internalization can trigger nuclear effects via "third messengers," offering new drug targets.
Area of Science:
- Cell Biology
- Molecular Pharmacology
- Neurobiology
Background:
- Cell surface receptors mediate intercellular communication and can desensitize via molecular and cellular mechanisms.
- Cellular desensitization involves rapid membrane receptor internalization in response to agonist excess.
- Internalized receptors may recycle or undergo degradation, but internalization also initiates retrograde signaling.
Purpose of the Study:
- To explore the concept of internalized receptors as
- third messengers
- facilitating retrograde signaling.
- To highlight the potential of these internalized receptor complexes as therapeutic targets.
Main Methods:
- The study is primarily conceptual, reviewing existing knowledge on receptor internalization and signaling.
- It discusses the mechanisms of receptor trafficking, including recycling and degradation pathways.
- It posits the role of ligand-receptor complexes in retrograde transport and nuclear signaling.
Main Results:
- Receptor internalization is not solely a degradation signal but can initiate retrograde signaling pathways.
- Internalized ligand-receptor complexes can act as
- third messengers
- , transported intracellularly to influence nuclear gene expression.
- These
- third messengers
- translocate to the nucleus, acting as transcriptional regulators.
Conclusions:
- Internalized receptors and their associated ligands represent a novel class of intracellular signaling molecules (
- third messengers
- ).
- These molecules can mediate long-term cellular effects by regulating gene expression.
- Targeting these
- third messengers
- presents a promising avenue for developing new therapeutic strategies.