Signal transduction via G protein coupled receptors: a personal outlook

Abstract

Intense research continues to address transmembrane signal transduction. Here we recall seven fundamental concepts governing this field. Only signal transduction via G protein coupled receptors (GPCR), is explicitly considered. But the fundamental concepts apply also to other transmembrane receptors such as receptor protein kinases. Although elements of the signal transduction complexes are readily exchangeable, it appears very likely that these complexes are highly organized in situ; how such organization is achieved remains puzzling, and an important question to be answered. Research in signal transduction can continue to explore with ‘reductionist’ approaches the fine details of individual molecular properties of signaling proteins and sub-cellular events. Attempts of comprehensive description of the biology of signal transduction cannot—at the present time—take into account the whole complexity of the systems involved. Nevertheless, it appears worthwhile to attempt more wholesome approaches, the results of which might turn out to be quite useful in medicine and pharmacology.

Keywords::

• G protein coupled receptors
• signal transduction
• guanine nucleotide-binding proteins
• systems biology
• intracellular messages

Acknowledgements

Lively discussions with Marie-Claude Blatter and Patricia Palagi from the Swiss Institute of Bioinformatics, with Susanna Cotecchia [Universities of Lausanne (Switzerland) and Bari (Italy)], and with Dermot Cooper (Cambridge University, UK) have made writing of this manuscript probably more instructive and entertaining than will be the reading.

Declaration of interest

The author acknowledges financial support from the Swiss National Science Foundation, and the Foundation pour Recherches Médicales.

Notes

1 Robert Schwyzer has illustrated the basic paradigm of signal transduction with the story ‘Little Jack should shake the pear tree’ (‘Joggeli söll ga Birli schüttle’). In this story, a whole set of successive elements are set up to spur little Jack to shake the pear tree: a dog should bite him, a stick should hit the dog, a fire should burn the stick, water should extinguish the fire, a calf should drink the water, and a butcher should slaughter the calf. But the whole chain of event is dormant until the master appears on the scene. Only then, the butcher goes after the calf, the calf after the water, the water after the fire etc. The agonist binding to the receptor was considered the ‘master’, since exclusively the agonist was considered to control the whole chain of signal transduction events.

2 The current manner to publish biological data often fragmented into single publications to optimize the sum of impact factors for a limited number of authors has serious drawbacks. Information structured is this manner is very difficult to extract and use in a more comprehensive context. In fact, it sometime appears that this century old system of individually signed scientific publications survives mainly because it serves firstly the commercial incentives of powerful editors, and secondly the need to rank individual researchers with H- and impact factors.

We may hope that the 21st century will see emerging more efficient ways to transmit scientific information. It will notably be of importance to improve the transmission of data. Although the ‘half-life’ (i.e. the average time interval between publication and citation) of scientific publications is continuously decreasing, data associated with them is currently deposited in uncontrolled quality and largely redundantly in repositories which claim to be ‘databases’. It is, e.g., rather striking that the quality of deposited data is of no importance for the acceptance of a publication even in scientific journals with the highest impact factors.

In analogy to the continuous and unchecked increase in the number of scientific journals, there is also an explosion of the number of databases The NAR database summary list, e.g., 10 databases with ‘signal transduction’ as keyword. Among them is ‘Pathguide’, a listing of 325 databases and other resources. The quality of some of these ‘resources’ is questionable; some listed are no longer available. Only a minority of the minor databases is continuously updated. In sum, without guidance, these resources cannot be efficiently used.

3 Reductionist approaches, a critical definition. When progressing from the description of the unperturbed system to the experimental test of a hypothesis, biological systems need to be markedly reduced in complexity. The tested property of a system is isolated by protein or organelle purification, pharmacological blockade of non-relevant events, displacement in model systems etc. This isolation changes any system, not only by reducing its complexity, but also by creating artificially a new and equally complex context. Excellent examples are gene knock-out (KO) and transgenic animals, for which a marked, sometimes decisive influence of the genetic background of the recipient animals is generally accepted, but rarely clarified. Current literature is still dominated by studies on ‘the function’ of a specific gene, usually based on the comparison of the wild type with the gene KO phenotype. It has been known for decades, that a single gene may produce a whole host of proteins for a whole host of functions by virtue of alternative splicing of the initial transcript and post-translational protein modifications. And therefore it is also a priori clear that KO studies cannot yield the right answer(s), since the question is erroneous. ‘Think simplicity, then discard it’(1)!