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Klinisk Biokemi i Norden · 4 2016
ATP as an extracellular signalling molecule
Karin Dreisig, Glostrup Research Institute, Rigshospitalet, Glostrup, Denmark
The role of adenosine trip-
hosphate (ATP) as an energy car-
rier in cellular functions is well
established and well described. It
was not until in the 1970s that the
transmitter function of ATP was
finally recognized after decades
of disagreement in the scientific
community. There are several good reasons why
ATP makes a powerful extracellular transmitter
molecule. Under normal conditions ATP is almost
negligible in the extracellular space, as opposed to
high levels inside the cell. ATP can be quickly relea-
sed from the cell to activate purinergic receptors and
ubiquitously expressed ecto-ATPases allow rapid
inactivation [1].
Mechanisms of ATP release
There are several ways ATP may be released from
the cells. These events range from strictly control-
led pathways to unconstrained events. ATP can be
released from the intracellular space following direct
rupture
of the cell membrane during pathological
conditions. These include, for example, ischemia,
bacterial invasion, or radiotherapy treatment [2, 3].
Rupture of cell membrane results in release of all of
the cells intracellular content. Depending on the cell
type and the location this may lead to mild to severe
inflammation in the surrounding tissue.
Several cell types are reported to express channels
that allow efflux of ATP. The blocking of membrane
channels with compounds such as carbenoxolone
shows attenuated and almost complete removal of
ATP release from cells, such as erythrocytes [4].
These findings suggest that ATP is released through
membrane channels by passive efflux driven by a
concentration gradient.
Active opening of channels can also permit release
of ATP from the cells. The main receptor families stu-
died in relation to channel-facilitated ATP release are
connexion hemichannels and pannexins [5]. These
channels span the cellular membrane connecting
the intra- and extracellular space to convey the pas-
sage of ions and small molecules such as ATP. The
mechanisms reporting opening of these channels are
controversial due to difficulties to clearly discrimi-
nate the contribution of each channel to the process.
Distinct pathways such as stretch or other secondary
messenger systems have been proposed for the activa-
tion of channels to facilitate the release of ATP to the
extracellular environment [6, 7].
A tightly controlled mechanism for ATP release is
exocytosis, which is the process of chemical release
after the fusion of secretory vesicles to the plasma
membrane. This process is most prominent in nerve
synapses where ATP is packed in transport vesicles
together with other neurotransmitters such as nore-
pinephrine and acetylcholine [8]. Exocytosis allows
rapid and targeted release of ATP at nerve terminals
to facilitate synaptic signalling.
ATP receptors
ATP receptors are expressed ubiquitously in the
human body. They belong to the receptor family
termed P2Y and P2X which are G-protein coupled
receptors and ion channels, respectively. The ATP
receptors regulate many normal processes in the body
and their dysfunction can result in many undesirable
outcomes.
At Glostrup Research Institute, Denmark, ATP
receptors formed the basis for various interesting
studies. The Molecular Sleep Group focuses on the
ATP receptor P2Y
11
. The rationale behind this comes
from the discovery of a genetic variant that has been
linked to the autoimmune sleep disorder narcolepsy
[9]. The ATP-sensing P2Y
11
receptor is usually descri-
bed as being involved in the regulation of the immune
system [10] and the group’s goal is to elucidate the
role of this receptor in the aetiology of narcolepsy.
Another ATP receptor, which we have studied
intensively, is P2X7 and its role in bone metabo-
lism. This is done in the Research Centre for Aging
