= Second messenger
A <second messenger> is a small intracellular <molecule> or <ion> that relays a received signal to target <proteins>. Its production, release, removal or binding changes its availability after signal reception. For a <cell-surface receptor>, distinguish the extracellular <ligand>, often called the first messenger, from the intracellular <second messenger>. An activated relay <protein> is not thereby a <second messenger>: the term identifies small chemical mediators, rather than every downstream component of <signal transduction>. https://pubmed.ncbi.nlm.nih.gov/27481708/[Newton, Bootman and Scott, Second Messengers (2016): definition and classes]{ref}
Two examples clarify what changes. A <biological cell> can make <cAMP> from <ATP>; alternatively, release of stored <calcium> <ions> can raise the free <calcium> <concentration> in its <cytoplasm>. The latter need not increase the total <calcium> content of the <biological cell>. Availability to target <proteins>, not merely the total amount present, carries the message. Removal and sequestration help terminate such signals. https://www.ncbi.nlm.nih.gov/books/NBK10794/[Purves et al., Neuroscience, 2nd edition: second messengers and calcium storage]{ref} <The Cell: A Molecular Approach, 2nd edition by Geoffrey M. Cooper/Pathways of Intracellular Signal Transduction>{ref}
The experimental motivation is unusually tangible: can a <hormone>'s effect be transferred to machinery that barely responds to the <hormone> itself? In Rall, Sutherland and Berthet's 1957 experiment, washed cat-liver particles were incubated with <ATP> and <magnesium> <ions>, with or without <epinephrine> and <glucagon>, two <hormones>. After five minutes at $30\,{}^{\circ}\mathrm C$, the mixtures were heated in boiling water for three minutes, chilled, and separated to remove insoluble material. Small samples of the clarified extracts were transferred to a separate soluble dog-liver preparation, again supplied with <ATP> and <magnesium> <ions>. The readout was the change in <glycogen phosphorylase> activity over five minutes, not the amount of newly synthesized <protein>. https://doi.org/10.1016/S0021-9258(18)65045-8[Rall, Sutherland and Berthet (1957), Figure 4 and pp. 470–471: preparation and transfer]{ref}
The <hormone>-conditioned extract caused a larger increase in <glycogen phosphorylase> activity. Water, extract made without <hormones>, and <hormones> added directly to the soluble preparation produced smaller effects. These comparisons distinguish transferred activity from baseline activity, preparation effects and simple <hormone> carryover. https://doi.org/10.1016/S0021-9258(18)65045-8[Rall, Sutherland and Berthet (1957), Figure 4: controls and observations]{ref}
\Image[/second-messenger-transfer.png]
{title=Separating <hormone> reception from a transferable intracellular effect}
{description=Original schematic of the classical extract-transfer experiment. Responses are qualitative comparisons, not reconstructed measurements; details of the separation and assay are abbreviated. See the primary references in the surrounding text.}
The inference is a transferable, heat-stable intermediary between the <hormone>-sensitive particles and the soluble machinery. This does not identify the intermediary merely from heat resistance, establish its direct target, or show that every <hormone> uses the same mechanism. Rall and Sutherland's 1958 paper reports the factor's identification as <cAMP> in accompanying chemical work, and follows its production from <ATP>. It also reports an important limit: washed heart and skeletal-muscle particles produced detectable <cAMP> with <epinephrine> under their test conditions, whereas brain particles produced similar amounts with and without it. Tissue and preparation matter. https://doi.org/10.1016/S0021-9258(19)77422-5[Rall and Sutherland (1958), introduction and Table IV: cAMP identity and tissue-dependent responses]{ref}
The useful and beautiful separation is between recognition and execution: an extracellular <ligand> can control intracellular <enzymes> through a chemically different intermediary. Making many <second messenger> <molecules> can support <signal amplification>, while different target <proteins> give the same mediator different consequences. A <second messenger> identifies a mode of relaying information; its presence alone does not specify the size or direction of the response. https://pubmed.ncbi.nlm.nih.gov/27481708/[Newton, Bootman and Scott (2016): second messengers and their targets]{ref}
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