First Messengers


First messengers are broadly defined as any extracellular factor that elicits a response within a cell. As such, first messengers are incredibly diverse, ranging from environmental factors, such as light or heat, to small molecules and peptides, up through large multivalent proteins. Although there are thousands of first messengers, there are relatively few classes of receptors that can receive these signals and elicit a response within the cell. These receptor classes are ion channels, intracellular receptors, G‐protein coupled receptors and single‐pass transmembrane receptors. Although some individual first messengers are well characterised, this article attempts to create a more cumulative reference of the first messengers most common to vertebrates.

Key Concepts:

  • All species use a form of cellular communication known as signal transduction to respond to first messengers in their external environment.

  • The diversity of molecules and stimuli that act as first messengers is vast.

  • The variety of receptors classes that detect these molecules is surprisingly limited considering the wide variety of ligands utilised.

  • Organisms use first messengers to receive information from the outside world as well as conduits for communication between cells.

Keywords: signal transduction; primary messenger; receptor; first messenger; hormone; sensory transduction; neurotransmitter; ligand; growth factor

Figure 1.

Diversity of first messengers. First messengers can range in size from environmental forces to multisubunit megadalton protein structures. When organised by size, several categories emerged, including environmental forces, ions/small molecules, metabolites, hormones, secreted proteins and extracellular matrix proteins. Some of the categories are fluid (indicated by grey areas). The mechanism's first messengers utilised to transmit information may be autocrine, paracrine, endocrine or synaptic. First messengers are either recognised by proteins on the cell surface including ion channels, G‐protein coupled receptors, enzyme‐linked or nonenzyme‐linked oligomeric receptors, may directly cross the cell membrane to affect internal cellular proteins.



Bankir L, Ahloulay M, Devreotes PN and Parent CA (2002) Extracellular cAMP inhibits proximal reabsorption: are plasma membrane cAMP receptors involved. American Journal of Physiology. Renal Physiology 282(3): 376–392.

Beato M and Sanchez‐Pacheco A (1996) Interaction of steroid hormone receptors with the transcription initiation complex. Endocrine Reviews 17(6): 587–609.

Bredt DS and Snyder SH (1992) Nitric oxide, a novel neuronal messenger. Neuron 8(1): 3–11.

Burdakov D, Luckman S and Verkhratsky A (2005) Glucose‐sensing neurons of the hypothalamus. Philosophical Transactions of The Royal Society B: Biological Sciences 360(1464): 2227–2235.

Cameron MJ and Kelvin DJ (2000) Cytokines, Chemokines and Their Receptors, 1st edn. Austin: Landes Bioscience.

Cohen S (2008) Origins of growth factors: NGF and EGF. Journal of Biological Chemistry 283(49): 33793–33797.

Conklin BR and Bourne HR (1994) Marriage of the flytrap and the serpent. Nature 367(6458): 22.

Egbuna OI and Brown EM (2008) Hypercalcaemic and hypocalcaemic conditions due to calcium‐sensing receptor mutations. Best Practice and Research Clinical Rheumatology 22(1): 129–148.

Egeblad M and Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nature Reviews. Cancer 2(3): 161–174.

Eyster KM (2007) The membrane and lipids as integral participants in signal transduction: lipid signal transduction for the non‐lipid biochemist. Advances in Physiology Education 31(1): 5–16.

Fernald RD (2008) The Senses: a Comprehensive Reference, 1st edn. Waltham: Academic Press.

Fields HL (1987) Pain. New York: McGraw‐Hill Book Company.

Fujita T (2002) Evolution of the lectin‐complement pathway and its role in innate immunity. Nature Reviews: Immunology 2(5): 346–353.

Gracheva EO, Ingolia NT, Kelly YM et al. (2010) Molecular basis of infrared detection by snakes. Nature 464(7291): 1006–1011.

Guharay F and Sachs F (1984) Stretch‐activated single ion channel currents in tissue‐cultured embryonic chick skeletal muscle. Journal of Physiology 352: 685–701.

Hegyi P and Rakonczay Z (2011) The role of nitric oxide in the physiology and pathophysiology of the exocrine pancreas. Antioxidants and Redox Signaling 15(10): 2723–2741.

Incardona JP, Gaffield W, Kapur RP and Roelink H (1998) The teratogenic veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development 125(18): 3553–3562.

Johnsen S and Lohmann KJ (2005) The physics and neurobiology of magnetoreception. Nature Reviews: Neuroscience 6(9): 703–712.

Kaul D (2003) Cholesterol‐receptor‐mediated genomics in health and disease. Trends in Molecular Medicine 9(10): 442–449.

Kolodkin AL and Tessier‐Lavigne M (2010) Mechanisms and molecules of neuronal wiring: a primer. Cold Spring Harbour Perspectives in Biology 3(6).

Latorre R, Brauchi S, Madrid R and Orio P (2011) A cool channel in cold transduction. Physiology 26(4): 273–285.

Layden B, Durai VL and Lowe W (2010) G‐protein‐coupled receptors, pancreatic islets, and diabetes. Nature Education 3(9): 13.

Locksley RM, Killeen N and Lenardo MJ (2001) The TNF and TNF receptor superfamilies: integrating mammalian Biology. Cell 104: 487–501.

Manger PR and Pettigrew JD (1995) Electroreception and the feeding behaviour of platypus (Ornithorhynchus anatinus: Monotremata: Mammalia). Philosophical Transactions of the Royal Society of London Series B Biological Sciences 347(347): 359–381.

Massarweh S, Osborne CK, Creighton CJ et al. (2008) Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Research 68(3): 826–833.

Meldrum DR, Gambone JC, Morris MA et al. (2011) The link between erectile and cardiovascular health: the canary in the coal mine. The American Journal of Cardiology 108(4): 599–606.

Mombaerts P (2004) Genes and ligands for odorant, vomeronasal and taste receptors. Nature Reviews: Neuroscience 5(4): 263–278.

Oren I, Fleishman SJ, Kessel A and Ben‐Tal N (2004) Free diffusion of steroid hormones across biomembranes: a simplex search with implicit solvent model calculations. Biophysical journal 87(2): 768–779.

Poehlmann T, Busch S, Mussil B et al. (2005) The possible Role of the JAK/STAT pathway in lymphocytes at the fetomaternal interface. Chemical Immunology and Allergy 89: 26–35.

Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103(2): 211–225.

Semenza GL (2004) Hydroxylation of HIF‐1: oxygen sensing at the molecular level. Physiology 19(4): 176–182.

Smith JW, Evans AT, Costall B and Smythe JW (2002) Thyroid hormones, brain function and cognition: a brief review. Neuroscience and Biobehavioral Reviews 26(1): 45–60.

Snyder SH and Ferris CD (2000) Novel neurotransmitters and their psychiatric relevance. American Journal of Psychiatry 157(11): 1738–1751.

Swyer GIM (1956) Some recent advances in endocrinology. British Medical Journal 2(4983): 5–10.

Tiligada E, Kyriakidis K, Chazot PL and Passani MB (2011) Histamine pharmacology and new CNS drug targets. CNS Neuroscience and Therapeutics 17(6): 620–628.

Volonté C, Amadio S, D'Ambrosi N, Colpi M and Burnstock G (2006) P2 receptor web: complexity and fine‐tuning. Pharmacology and Therapeutics 112(1): 264–280.

Wang M, Wong AH and Liu F (2012) Interactions between NMDA and dopamine receptors: a potential therapeutic target. Brain Research. Epub ahead of print.

Wooding S (2011) Signatures of natural selection in a primate bitter taste receptor. Journal of Molecular Evolution 73(5‐6): 257–265.

Yau KW and Hardie RC (2009) Phototransduction motifs and variations. Cell 139(2): 246–264.

Zlotnik A and Yoshie O (2000) Chemokines: a new classification system and their role in immunity. Immunity 12(2): 121–127.

Further Reading

Angers S and Moon R (2009) Proximal events in Wnt signal transduction. Nature Reviews: Molecular Cell Biology 10(7): 468–477.

McKay MM and Morrison DK (2007) Integrating signals from RTKs to ERK/MAPK. Oncogene 26(22): 3113–3121.

Pawson T (1997) Signaling through scaffold, anchoring, and adaptor proteins. Science 5346(278): 2075–2080.

Scott JD and Pawson T (2000) Cell communication: the inside story. Scientific American 282(6): 54–61.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Kodis, Erin J, Smindak, Richard J, Kefauver, Jennifer M, Heffner, Danielle L, Aschenbach, Krista L, Brennan, Elliot R, Chan, Kelvin, Gamage, Kanchana K, Lambeth, Philip S, Lawler, Jessica R, Sikora, Arthur K, Vercruysse, Nicholas R, and Deppmann, Christopher D(Oct 2012) First Messengers. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024167]