Cell signaling in multicellular organisms
In a multicellular organism, signaling between cells occurs either through release into the extracellular space, divided in paracrine signaling (over short distances) and endocrine signaling (over long distances), or by direct contact, known as juxtacrine signaling. Autocrine signaling is a special case of paracrine signaling where the secreting cell has the ability to respond to the secreted signaling molecule. Synaptic signaling is a special case of paracrine signaling (for chemical synapses) or juxtacrine signaling (for electrical synapses) between neurons and target cells. Signaling molecules interact with a target cell as a ligand to cell surface receptors, and/or by entering into the cell through its membrane or endocytosis for intracrine signaling. This generally results in the activation of second messengers, leading to various physiological effects.
A particular molecule is generally used in diverse modes of signaling, and therefore a classification by mode of signaling is not possible. At least three important classes of signaling molecules are widely recognized, although non-exhaustive and with imprecise boundaries, as such membership is non-exclusive and depends on the context:
- Hormones are the major signaling molecules of the endocrine system, though they often regulate each other's secretion via local signaling (e.g. islet of Langerhans cells), and most are also expressed in tissues for local purposes (e.g. angiotensin) or failing that, structurally related molecules are (e.g. PTHrP).
- Neurotransmitters are signaling molecules of the nervous system, also including neuropeptides and neuromodulators. Neurotransmitters like the catecholamines are also secreted by the endocrine system into the systemic circulation.
- Cytokines are signaling molecules of the immune system, with a primary paracrine or juxtacrine role, though they can during significant immune responses have a strong presence in the circulation, with systemic effect (altering iron metabolism or body temperature). Growth factors can be considered as cytokines or a different class.
Signaling molecules can belong to several chemical classes: lipids, phospholipids, amino acids, monoamines, proteins, glycoproteins, or gases. Signaling molecules binding surface receptors are generally large and hydrophilic (e.g. TRH, Vasopressin, Acetylcholine), while those entering the cell are generally small and hydrophobic (e.g. glucocorticoids, thyroid hormones, cholecalciferol, retinoic acid), but important exceptions to both are numerous, and a same molecule can act both via surface receptor or in an intracrine manner to different effects. In intracrine signaling, once inside the cell, a signaling molecule can bind to intracellular receptors, other elements, or stimulate enzyme activity (e.g. gasses). The intracrine action of peptide hormones remains a subject of debate.
Hydrogen sulfide is produced in small amounts by some cells of the human body and has a number of biological signaling functions. Only two other such gases are currently known to act as signaling molecules in the human body: nitric oxide and carbon monoxide.
Intraspecies and interspecies signaling
Molecular signaling can occur between different organisms, whether unicellular or multicellular, the emitting organism produces the signaling molecule, secrete it into the environment, where it diffuses, and it is sensed or internalized by the receiving organism. In some cases of interspecies signaling, the emitting organism can actually be a host of the receiving organism, or vice-versa.
Intraspecies signaling occurs especially in bacteria, yeast, social insects, but also many vertebrates. The signaling molecules used by multicellular organisms are often called pheromones, they can have such purposes as alerting against danger, indicating food supply, or assisting in reproduction. In unicellular organisms such as bacteria, signaling can be used to 'activate' peers from a dormant state, enhance virulence, defend against bacteriophages, etc. In quorum sensing, which is also found in social insects, the multiplicity of individual signals has the potentiality to create a positive feedback loop, generating coordinated response, in this context the signaling molecules are called autoinducers. This phenomenon is similar to the autocrine co-stimulation of multicellular organisms, on the other hand cellular differentiation occurs in bacteria, with altered response to peer signals, demonstrating a similarity with paracrine signaling of multicellular organisms. This signaling mechanism may have been involved in evolution from unicellular to multicellular organisms. Bacteria also use contact-dependent signaling, notably to limit their growth.
Molecular signaling can also occur between individuals of different species, this has been particularly studied in bacteria. Different bacterial species can coordinate to colonize a host and participate in common quorum sensing. Therapeutic strategies to disrupt this phenomenon are being investigated. Interactions mediated through signaling molecules are also thought to occur between the gut flora and their host, as part of their commensal or symbiotic relationship.
- Gilbert, Scott F. (2000). "Juxtacrine Signaling". In NCBI bookshelf. Developmental biology (6. ed.). Sunderland, Mass.: Sinauer Assoc. ISBN 0878932437.
- Bruce Alberts et al (2002). "General Principles of Cell Communication". In NCBI bookshelf. Molecular biology of the cell (4th ed.). New York: Garland Science. ISBN 0815332181.
- Re, R (1999 Oct). "The nature of intracrine peptide hormone action". Hypertension 34 (4 Pt 1): 534–8. doi:10.1161/01.HYP.34.4.534. PMID 10523322.
- Hausman, Geoffrey M. Cooper, Robert E. (2000). "Signaling Molecules and Their Receptors". In NCBI bookshelf. The cell : a molecular approach (2nd ed.). Washington, D.C.: ASM Press. ISBN 087893300X.
- Tirindelli, R; Dibattista, M; Pifferi, S; Menini, A (2009 Jul). "From pheromones to behavior". Physiological reviews 89 (3): 921–56. doi:10.1152/physrev.00037.2008. PMID 19584317.
- Mukamolova, GV; Kaprelyants, AS; Young, DI; Young, M; Kell, DB (1998 Jul 21). "A bacterial cytokine". Proceedings of the National Academy of Sciences of the United States of America 95 (15): 8916–21. doi:10.1073/pnas.95.15.8916. PMC 21177. PMID 9671779.
- Miller, Melissa B.; Bassler, Bonnie L. (1 October 2001). "Quorum sensing in bacteria". Annual Review of Microbiology 55 (1): 165–199. doi:10.1146/annurev.micro.55.1.165. PMID 11544353.
- Kaper, JB; Sperandio, V (2005 Jun). "Bacterial cell-to-cell signaling in the gastrointestinal tract". Infection and immunity 73 (6): 3197–209. doi:10.1128/IAI.73.6.3197-3209.2005. PMC 1111840. PMID 15908344.
- Camilli, A.; Bonnie L. Bassler (24 February 2006). "Bacterial Small-Molecule Signaling Pathways". Science 311 (5764): 1113–1116. doi:10.1126/science.1121357. PMC 2776824. PMID 16497924.
- Lopez, D.; Vlamakis, H.; Losick, R.; Kolter, R. (15 July 2009). "Paracrine signaling in a bacterium". Genes & Development 23 (14): 1631–1638. doi:10.1101/gad.1813709.
- Stoka, AM (1999 Jun). "Phylogeny and evolution of chemical communication: an endocrine approach". Journal of molecular endocrinology 22 (3): 207–25. doi:10.1677/jme.0.0220207. PMID 10343281.
- Aoki, SK; Pamma, R; Hernday, AD; Bickham, JE; Braaten, BA; Low, DA (2005 Aug 19). "Contact-dependent inhibition of growth in Escherichia coli". Science 309 (5738): 1245–8. doi:10.1126/science.1115109. PMID 16109881.
- Blango, Matthew G; Mulvey, Matthew A (31 March 2009). "Bacterial landlines: contact-dependent signaling in bacterial populations". Current Opinion in Microbiology 12 (2): 177–181. doi:10.1016/j.mib.2009.01.011. PMC 2668724. PMID 19246237.
- Shank, Elizabeth Anne; Kolter, Roberto (31 March 2009). "New developments in microbial interspecies signaling". Current Opinion in Microbiology 12 (2): 205–214. doi:10.1016/j.mib.2009.01.003. PMC 2709175. PMID 19251475.
- Ryan, R. P.; Dow, J. M. (1 July 2008). "Diffusible signals and interspecies communication in bacteria". Microbiology 154 (7): 1845–1858. doi:10.1099/mic.0.2008/017871-0.
- Ryan, Robert P.; Dow, J. Maxwell (28 February 2011). "Communication with a growing family: diffusible signal factor (DSF) signaling in bacteria". Trends in Microbiology 19 (3): 145–152. doi:10.1016/j.tim.2010.12.003. PMID 21227698.
- Déziel, E; Lépine, F; Milot, S; He, J; Mindrinos, MN; Tompkins, RG; Rahme, LG (2004 Feb 3). "Analysis of Pseudomonas aeruginosa 4-hydroxy-2-alkylquinolines (HAQs) reveals a role for 4-hydroxy-2-heptylquinoline in cell-to-cell communication". Proceedings of the National Academy of Sciences of the United States of America 101 (5): 1339–44. doi:10.1073/pnas.0307694100. PMC 337054. PMID 14739337.
- Federle, Michael J.; Bassler, Bonnie L. (31 October 2003). "Interspecies communication in bacteria". Journal of Clinical Investigation 112 (9): 1291–1299. doi:10.1172/JCI20195. PMC 228483. PMID 14597753.
- Sperandio, V.; et al (14 July 2003). "Bacteria-host communication: The language of hormones". Proceedings of the National Academy of Sciences 100 (15): 8951–8956. doi:10.1073/pnas.1537100100. PMC 166419.
- Hooper, LV; Gordon, JI (2001 May 11). "Commensal host-bacterial relationships in the gut". Science 292 (5519): 1115–1118. doi:10.1126/science.1058709. PMID 11352068.