There are 1000 7TM receptors, for example, but many of them exert their effects through G proteins which increase the cAMP in the cell. When cAMP increases, the cell reacts. But if two receptors on the same cell work through the cAMP pathway, how does the cell know what to do when cAMP rises? Is each cell specific to a single receptor that acts through the cAMP pathway? And if that is the case, how is the response determined during the development or maturation of the cell? I understand this could potentially be a huge topic. I'm just looking for a paragraph or two that could point my thinking in the right direction.
Hello Jennifer Washburn
It is indeed a huge topic. But these few lines below may perhaps get you thinking in the right direction. I have also attached two articles, which may be helpful!
During development, signaling pathways specify cell fates by activating transcriptional programs in response to extracellular signals. The response of a given cell to a signal depends on its amplitude, duration, interactions between pathways, and integration of transcription factor effectors at promoters and enhancers of target genes. It may also be predetermined by the set of transcription factors expressed in the cell at the time the signal is received.
When the ligands bind to transmembrane receptors on target cells, they activate a cascade of events that ultimately regulate the activity of a small number of transcription factors and/or cofactors, triggering gene-expression programs that drive the cellular changes.
The integration of signaling pathways at the promoter/enhancer level allows each gene to define its “rules” of regulation, according to the tissue setting in which it is activated. Two given pathways can act synergistically in one setting and antagonistically in another setting. Thus, there may be only a small number of signaling pathways that are used during development, but the combinatorial flexibility at the promoter level generates a vast array of possible responses.
In the developmental signaling pathways, ligand-receptor interactions activate intracellular effectors, which then regulate target gene expression. Intracellular signaling activity also induces a myriad of feedback loops to further modulate the signal processing capability of the pathway.
At the single cell level, pathways can sense the molecular identity and concentration of individual ligands, the relative concentrations of multiple ligands (combinations) or the temporal dynamics of ligand concentration. While at the tissue level, signaling pathways can actively modulate the distribution of extracellular ligands and intracellular signal perception in space and time.
Cells appear to selectively sense specific ligands, even when multiple ligands can signal through the same receptors. One way this is achieved is through pathway modulators, such as co-receptors and enzymes that inhibit or facilitate binding between specific ligands and receptors, and thus alter communication specificity.
Receptor Tyrosine Kinase (RTK) signaling systems play pivotal role across an astonishingly broad range of developmental processes. Different RTK pathways share a common set of intracellular signal transduction components but induce different cellular responses.
For instance, both epiregulin (EREG) and EGF share the same receptor EGFR, but EREG promotes differentiation whereas EGF promotes proliferation in MCF-7 cells because EREG elicits sustained phosphorylation of ERK (pERK) whereas EGF induces transient pERK.
Please refer to the articles attached below for more information on this topic.
https://journals.biologists.com/dev/article/146/12/dev170977/19447/Communication-codes-in-developmental-signaling
Article Signaling Mechanisms Controlling Cell Fate and Embryonic Patterning
Best.
Hello Jennifer Washburn,
I thoroughly agree with Malcolm Nobre’s response.
Another way cells regulate responses to ligands is through their shape at the time of stimulation and/or the extracellular matrix (ECM) they are on. Responses to ligands in 2D culture are often very different to those in a 3D configuration and different yet still to those on different ECMs.
It’s enough to make your head spin!
Jennifer, a valid answer to your question immediately won the Nobel price :-)
Your question is absolutely relevant to understand how cells are functioning. Just considering GPCR, as you wrote, there are about 800 independent sequences, though more than half of them are involved in smell sensation. There is an estimation of how many different signals can be sensed by GPCR: ~30-100000. As you raised, how come that these many different inputs can be translated to proper cellular responses, regulating the expression of 20000 genes, by utilizing actually 3 second messengers: intracellular free Ca2+, cAMP, and the activation of G12/13. It is literally impossible to explain this only with compartmentalization, which might affect though the functional outcome of the original signals. But the extent of information shlould be in the same range during the whole signaling processes, so the tenthousends of inputs, which results in tenthousends of outputs, should involve tenthousends of poossibilities during the whole process. The only way it is possible is the coding of the input signals, into the numerous spatio-temporal activation shapes of the second messengers. e.g. different shapes of transients and waves of the second messengers' intracellular concentrations, which somehow integrates on the next coding on the transcription factors, etc... So, in my opinion, there is noe definitive answer to your question right now, but this is oone of the most interesting, exciting, and important problems in current biology research.
Best, Karoly
- Badges
- Science topic
- Similar topics
- Linguistics
- Composition Studies
- Publication