Thursday, June 4, 2009

Adding a Dimension to Intercell Signaling

I've discussed the cell's internal computing abilities, and mentioned how it ties to the signaling between cells, but the general assumption in intercell signaling has been that one signaling molecule represents a scalar message: a one-dimensional number represented by concentration. In principle, any two molecules could be combined to create a 2-dimensional signal, representing a point on a plane, but in a preprint article1 we hear of an actual 2-dimensional receptor: one molecule embedded in the cell's membrane that has two specific reactions within the cell to ligands outside, and the amount of those reactions depends on the ligand involved.

Zidar, D., Violin, J., Whalen, E., & Lefkowitz, R. (2009). Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0904361106

A Bit About G Proteins and GPCRs

Let's start with some background regarding "G proteins", short for guanine nucleotide-binding proteins. These proteins "plug into" the "G-socket system": that is they use GTP as a power source, acting as "second messengers" for signals from outside the cell. Typically, a G protein will be bound in a trimer: a combination of three molecules, usually all different. When the ligand outside the cell binds to the receptor it changes its shape, transmitting its message through the membrane where the new shape can cause the G protein trimer to split into a dimer and a singleton, each of which may now act to catalyse internal signal reactions.

Figure 1: Signal Transduction that uses G Proteins. Click image to see original caption. (From Ref 3.)

These receptors are called G protein-coupled receptors (GPCRs), and they form one big, highly conserved, family.1 They are a subset (or sometimes used interchangeably) of seven-transmembrane receptors (7TMRs), one of the oldest types of protein.7, 8

Once the ligand is bound, the new receptor shape is also vulnerable to phosphorylation by enzymes called G protein–coupled receptor kinases (GRKs), which represents a further change to the receptor. Next, the phosphorylated receptor will bind a type of molecule called a ß-arrestin, which pretty much neutralizes the receptor. In many cases it also pulls the receptor out of the cell membrane, internalizing it into a vesicle or endosome.

Figure 2: Model of ß-arrestin-regulated internalization of a prototypic GPCR. Click on image to see original caption. (From Ref 5.)

The ß-arrestin-bound receptor can also act as a signaling molecule, catalyzing further changes.2, 3 Further, the ß-arrestin, after binding to the GPCR, can:
translocate from the cytoplasm to the nucleus and associate with transcription cofactors such as p300 and cAMP-response element-binding protein (CREB) at the promoters of target genes to promote transcription. They also interact with regulators of transcription factors, such as IκBα and MDM2, in the cytoplasm and regulate transcription indirectly. This ß-arrestin-mediated regulation of transcription appears to play important roles in cell growth, apoptosis and modulation of immune functions.2
The New Discovery

These two paths have been regarded as "tied together": when the ligand bound to the GPCR, it set off both paths of reaction. The second path, based on phosphorylation of the receptor, tends to reduce its power, allowing it to "desensitize" itself to the incoming signal: an important feature of many sensory systems. However, Zidar et al.1 have demonstrated that a GPCR called C-C chemokine receptor type 7 (CCR7) responds differently to two natural ligands: Chemokine (C-C motif) ligand 19 (CCL19), and Chemokine (C-C motif) ligand 21 (CCL21):
CCL19 leads to robust CCR7 phosphorylation and ß-arrestin2 recruitment catalyzed by both GRK3 and GRK6 whereas CCL21 activates GRK6 alone. This differential GRK activation leads to distinct functional consequences. Although each ligand leads to ß-arrestin2 recruitment, only CCL19 leads to redistribution of ß-arrestin2-GFP into endocytic vesicles and classical receptor desensitization. In contrast, these agonists are both capable of signaling through GRK6 and ß-arrestin2 to ERK kinases. Thus, this mechanism for ‘‘ligand bias’’ whereby endogenous agonists activate different GRK isoforms leads to functionally distinct pools of ß-arrestin.1
We don't really have to understand everything in the blockquote (from the abstract, there's more explanation in the main text), we just need to see that the amount of reaction along each of the two paths in (our) Figure 1 is different for CCL19 and CCL21. This is functionally equivalent to a 2-dimensional signal, that can be emitted by any cell(s) that can vary their relative rates of secretion of these two ligands depending on internal calculations. If there are many cells emitting such signals, they will be roughly additive (depending on distance for diffusion and mixing).

The complexity of the signaling network within the body is well known, but this (literally) adds a whole new dimension to what it's capable of.

Links: Not all of these are called out in the text. Use the back key if you came via a footnote.

1. Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands

2. ß-arrestin signaling and regulation of transcription

3. Transduction of Receptor Signals by ß-Arrestins

4. Regulation of G Protein-Coupled Receptor Kinases and Arrestins During Receptor Desensitization

5. Arrestin-Independent Internalization of G Protein-Coupled Receptors

6. GRKs and arrestins: regulators of migration and inflammation

7. Application of comparative genomics in the identification and analysis of novel families of membrane-associated receptors in bacteria

8. On the origins of arrestin and rhodopsin

9. Phylogenetic analysis of 277 human G-protein-coupled receptors as a tool for the prediction of orphan receptor ligands

1 comment:

  1. Intercellular calcium waves in central nervous system astrocyte networks underline the principle mechanism of cell signaling in astrocyte syncsytiums, which putatively contribute to the modulation of neuronal signaling and metabolic regulation. Also its ability to design and construct synthetic gene regulatory networks offers the prospect of studying issues related to cellular function in a simplified context. Thanks for posting this informative article.