Calcium, inositol triphosphate and diacylglycerol
This chapter is related to the aims of Section C(iv) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "explain receptor activity with regard to... second messengers and G proteins". Of the second messenger systems, ionised calcium is probably the most widespread. There is no cell in the body which would not use intracellular calcium signalling for one thing or another. In the presence of calcium, virtually all proteins will undergo some sort of change. In this, the use of calcium is not unique to humans or even mammals, but common to all multicellular life. In their ode to the second messenger functions of calcium, Carafoli and Krebs (2016) mention that it ows its ubiquity to the combination of easy availability to early life (it is the third most abundant metal on Earth) and to its relatively low concentration in the primordial sea, which made it more effective as a messenger molecule (in contrast, magnesium ions were everywhere, making them much too common to use as specific signals). Plus, where calcium and magnesium are both suitable actors (eg. some sort of promiscuous cation-binding site) the calcium usually reacts about 100 times faster than magnesium, making it a more effective messenger (Verkhratski et al, 2014)
This topic has never come up in the CICM primary exam, which makes this chapter an unlikely candidate to feature prominently during the final pre-dawn hours of the cramming trainee. That time is better spent on something which attracts more marks. For the purposes of vaguely knowing something examinable about calcium second messenger systems, the following brief summary is sufficient:
If one needs to know more for some non-exam-related reason, there is ample literature available on the subject. Of the published reviews, Makoto Endo's 2006 paper is probably the best in terms of being a good balance of detailed and concise.
Calcium as a second messenger
Intracellular calcium concentration is kept at a nanomolar level- generaly some decimal fractions of a nanomole. Calcium is actively pumped out of the cell, and actively sequestered in intracellular stores.
The entry of calcium into the cell is usually mediated by the actions of phospholipase C. The crucial stage of this process is the activation of Phospolipase C (beta or gamma) by some means - usually by a G-protein coupled receptor or a receptor with tyrosine kinase activity (an intracellular receptor domain or a soluble form of tyrosine kinase). Phospholipase C (β) is activated by G-protein-coupled receptors, whereas phospholipase C (γ) is activated by the tyrosine kinase pathway. Either way, the result is the hydrolysis of a membrane phospholipid PIP2, phosphatidylinositol 4,5-bisphosphate. The results of the hydrolysis is production of inositol triphosphate (IP3) and diacylglycerol (DAG), i.e. both molecules are produced by this reaction.
IP3 and DAG then go on to have distal effects. DAG is strongly hydrophobic and remains in the membrane, whereas IP3 can diffuse away and perform useful actions elsewhere. Of these molecules, IP3 is the one responsible for bringing calcium into the cell, whereas DAG has several other effects, many of which are facilitated by the availability of intracellular calcium.
When IP3 releases calcium:
Calcium release causes activation of calmodulin-sensitive enzymes:
- Phosphodiesterase (yes, the one that degrades cAMP and cGMP)
- Myosin light chain Kinase which allows muscle contraction to begin by enabling the formation of the actin-myosin crossbridge
- Calmodulin-dependent protein kinase (I and II) involved in calcium homeostasis, long term memory formation, CD-8 T-cell activation, chloride transport in epithelia, neuronal transmission, cilia motility, apoptosis, regulation of various enzymes, etc etc
When DAG is activated
It in turn activates Protein Kinase C. This thing has multitudes of effects.
- α-1 adrenoreceptor mediated contraction of smooth muscle
- α-1 adrenoceptor mediated ejaculation
- Prostaglandin and thromboxane mediated contraction of smooth muscle
- Muscarinic M3 receptor mediated contraction of smooth muscle
References
Endo, Makoto. "Calcium ion as a second messenger with special reference to excitation-contraction coupling." Journal of pharmacological sciences 100.5 (2006): 519-524.
Verkhratsky, Alexei, and Vladimir Parpura. "Calcium signalling and calcium channels: evolution and general principles." European journal of pharmacology 739 (2014): 1-3.
Carafoli, Ernesto, and Joachim Krebs. "Why calcium? How calcium became the best communicator." Journal of Biological Chemistry 291.40 (2016): 20849-20857.
Berridge, Michael J. "Inositol trisphosphate and calcium signalling." Nature 361.6410 (1993): 315.
Berridge, Michael J. "Inositol trisphosphate and calcium signalling mechanisms." Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 1793.6 (2009): 933-940.
Berridge, Michael J., and Robin F. Irvine. "Inositol phosphates and cell signalling." Nature 341.6239 (1989): 197.
Tewson, Paul, et al. "Simultaneous detection of Ca2+ and diacylglycerol signaling in living cells." PLoS One 7.8 (2012): e42791.