65
5
for the profound influence that caffeine has on molluscs, various insects and spiders
(Mustard 2014). Spiders react with widely irregular spider nets when exposed to caffeine
(but also to marijuana, amphetamine and GABA agonists; see 7 Sect. 7.3 in 7 Chap. 7,
7 Box7.1). The reason for this is unclear. However, the expected increase in cAMP levels
may have an effect on the spiders’ memory. In analogy, as has already been shown 30 years
ago, mutations in the dunce gene encoding a Drosophila phosphodiesterase and thereby
also causing high cAMP levels, lead to deficiencies in learning and memory in flies (Davis
et al. 1995).
Caffeine was also demonstrated a long time ago to bind to ryanodine receptors in
skeletal muscle. Caffeine at concentrations between 0.5 and 30 mM shifted the Ca 2+ -
concentration threshold for channel opening to lower values, making the ryanodine
receptor more sensitive (Pessah et al. 1987). Caffeine interactions with the single ryanodine receptor isoform from several invertebrate species have now also been reported
(Mustard 2014).
In humans, the main actions of caffeine are attributed to its antagonistic action on
adenosine receptors. This is suggested by the low concentration of caffeine between 1 and
10 μM that is needed to inactivate adenosine receptor signalling. In comparison with the
effects on phosphodiesterases and ryanodine receptors, this is at least 1000-fold less
(Mustard 2014). A metabolic product of caffeine degradation is theophylline, which is also
found in plants that produce caffeine, but in lower concentrations. Theophylline, like caffeine, antagonizes adenosine receptors. However, it also has several other clinically relevant targets in cells, e.g. it is an inhibitor of phosphodiesterases (PDE3 and 4) at low
concentrations, and it activates histone-deacetylase 2 and inhibits the inflammatory transcription factor NFκB (Barnes 2013).
The endogenous ligand (receptor agonist) for adenosine receptors is adenosine. It is
produced in cells from AMP – the degradation product of ATP – by 5’nucleotidase. This
reaction is antagonized by adenosine kinase. Extracellular adenosine is produced from
ATP, which is secreted as transmitter or co-transmitter and hydrolysed outside the cell.
Adenosine transporters let adenosine pass through the membranes of nerve and glia cells,
thus establishing the equilibrium between extra- and intracellular adenosine. Under conditions of sufficient energy supply in cells, adenosine kinase activity is high, and therefore
the adenosine concentration inside the cell is low, making transporters work inwardly.
However, at high-energy demand, when the intracellular ATP levels decrease, activity of
adenosine kinase is low, adenosine concentration inside raises and the transporters work
outwardly. As a result, more adenosine is found outside the cell and available for activating
adenosine receptors. In this way, adenosine receptors signal in an energy-dependent way
(. Fig. 5.4). Minor changes in steady-state ATP levels in brain cells (normally 5 mM) can
therefore lead to relatively major changes in the extracellular adenosine concentration,
which is normally low with 30–200 nM (Landolt 2008). Such changes can be induced by
hypoxia, exercise, high altitude and exhaustion. Adenosine receptor signalling induces
appropriate physiological and psychological responses. These include sleep regulation, the
modulation of motor activity through the dopaminergic system and flavour preferences
(Huang et al. 2011).
Adenosine also has some psycho-stimulatory effects. These seem to depend on its
interaction with the dopaminergic neurotransmitter system (Ferre 2010). Yet, caffeine is
neither considered addictive nor classified in any of the schedules of the Controlled
Substances Act in US legislation for the Single Convention on Narcotic Drugs of 1961,
which is an international treaty for controlling production and supply of specific drugs
5.3 · Adenosine Receptors: Caffeine
5
for the profound influence that caffeine has on molluscs, various insects and spiders
(Mustard 2014). Spiders react with widely irregular spider nets when exposed to caffeine
(but also to marijuana, amphetamine and GABA agonists; see 7 Sect. 7.3 in 7 Chap. 7,
7 Box7.1). The reason for this is unclear. However, the expected increase in cAMP levels
may have an effect on the spiders’ memory. In analogy, as has already been shown 30 years
ago, mutations in the dunce gene encoding a Drosophila phosphodiesterase and thereby
also causing high cAMP levels, lead to deficiencies in learning and memory in flies (Davis
et al. 1995).
Caffeine was also demonstrated a long time ago to bind to ryanodine receptors in
skeletal muscle. Caffeine at concentrations between 0.5 and 30 mM shifted the Ca 2+ -
concentration threshold for channel opening to lower values, making the ryanodine
receptor more sensitive (Pessah et al. 1987). Caffeine interactions with the single ryanodine receptor isoform from several invertebrate species have now also been reported
(Mustard 2014).
In humans, the main actions of caffeine are attributed to its antagonistic action on
adenosine receptors. This is suggested by the low concentration of caffeine between 1 and
10 μM that is needed to inactivate adenosine receptor signalling. In comparison with the
effects on phosphodiesterases and ryanodine receptors, this is at least 1000-fold less
(Mustard 2014). A metabolic product of caffeine degradation is theophylline, which is also
found in plants that produce caffeine, but in lower concentrations. Theophylline, like caffeine, antagonizes adenosine receptors. However, it also has several other clinically relevant targets in cells, e.g. it is an inhibitor of phosphodiesterases (PDE3 and 4) at low
concentrations, and it activates histone-deacetylase 2 and inhibits the inflammatory transcription factor NFκB (Barnes 2013).
The endogenous ligand (receptor agonist) for adenosine receptors is adenosine. It is
produced in cells from AMP – the degradation product of ATP – by 5’nucleotidase. This
reaction is antagonized by adenosine kinase. Extracellular adenosine is produced from
ATP, which is secreted as transmitter or co-transmitter and hydrolysed outside the cell.
Adenosine transporters let adenosine pass through the membranes of nerve and glia cells,
thus establishing the equilibrium between extra- and intracellular adenosine. Under conditions of sufficient energy supply in cells, adenosine kinase activity is high, and therefore
the adenosine concentration inside the cell is low, making transporters work inwardly.
However, at high-energy demand, when the intracellular ATP levels decrease, activity of
adenosine kinase is low, adenosine concentration inside raises and the transporters work
outwardly. As a result, more adenosine is found outside the cell and available for activating
adenosine receptors. In this way, adenosine receptors signal in an energy-dependent way
(. Fig. 5.4). Minor changes in steady-state ATP levels in brain cells (normally 5 mM) can
therefore lead to relatively major changes in the extracellular adenosine concentration,
which is normally low with 30–200 nM (Landolt 2008). Such changes can be induced by
hypoxia, exercise, high altitude and exhaustion. Adenosine receptor signalling induces
appropriate physiological and psychological responses. These include sleep regulation, the
modulation of motor activity through the dopaminergic system and flavour preferences
(Huang et al. 2011).
Adenosine also has some psycho-stimulatory effects. These seem to depend on its
interaction with the dopaminergic neurotransmitter system (Ferre 2010). Yet, caffeine is
neither considered addictive nor classified in any of the schedules of the Controlled
Substances Act in US legislation for the Single Convention on Narcotic Drugs of 1961,
which is an international treaty for controlling production and supply of specific drugs
5.3 · Adenosine Receptors: Caffeine