Inside job: ligand-receptor pharmacology beneath the plasma membrane
Abstract
Joseph J BABCOCK, Min LI*
The Solomon H. Snyder Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center (JHICC), School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
Most drugs acting on the cell surface receptors are membrane permeable and thus able to engage their target proteins in different subcellular compartments. However, these drugs’ effects on cell surface receptors have historically been studied on the plasma membrane alone. Increasing evidence suggests that small molecules may also modulate their targeted receptors through membrane trafficking or organelle-localized signaling inside the cell. These additional modes of interaction have been reported for functionally diverse ligands of GPCRs, ion channels, and transporters. Such intracellular drug-target engagements affect cell surface expression. Concurrent intracellular and cell surface signaling may also increase the complexity and therapeutic opportunities of small molecule modulation. Here we discuss examples of ligand-receptor interactions that are present in both intra- and extracellular sites, and the potential therapeutic opportunities presented by this phenomenon.
Keywords: ligand-receptor interaction; phamacological chaperone; endoplasmic reticulum; GPCR; ion channel; transporter
We thank Henry LESTER for valuable advice, the Min LI’s laboratory for valuable discussions and Alison Neal for editorial assistance. This work is supported by grants to Min LI from the National Institutes of Health (GM078579 and MH084691).
* To whom correspondence should be addressed.
E-mail minli@jhmi.edu
Received 2013-03-04 Accepted 2013-04-07
Keywords:
The Solomon H. Snyder Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center (JHICC), School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
Most drugs acting on the cell surface receptors are membrane permeable and thus able to engage their target proteins in different subcellular compartments. However, these drugs’ effects on cell surface receptors have historically been studied on the plasma membrane alone. Increasing evidence suggests that small molecules may also modulate their targeted receptors through membrane trafficking or organelle-localized signaling inside the cell. These additional modes of interaction have been reported for functionally diverse ligands of GPCRs, ion channels, and transporters. Such intracellular drug-target engagements affect cell surface expression. Concurrent intracellular and cell surface signaling may also increase the complexity and therapeutic opportunities of small molecule modulation. Here we discuss examples of ligand-receptor interactions that are present in both intra- and extracellular sites, and the potential therapeutic opportunities presented by this phenomenon.
Keywords: ligand-receptor interaction; phamacological chaperone; endoplasmic reticulum; GPCR; ion channel; transporter
We thank Henry LESTER for valuable advice, the Min LI’s laboratory for valuable discussions and Alison Neal for editorial assistance. This work is supported by grants to Min LI from the National Institutes of Health (GM078579 and MH084691).
* To whom correspondence should be addressed.
E-mail minli@jhmi.edu
Received 2013-03-04 Accepted 2013-04-07