Abstract
Neural circuit activity increases the release of the purine neuromodulator adenosine into the extracellular space leading to A1 receptor activation and negative feedback via membrane hyperpolarization and inhibition of transmitter release. Adenosine can be released by a number of different mechanisms that include Ca2+ dependent processes such as the exocytosis of ATP. During sustained pathological network activity, ischemia and hypoxia the extracellular concentration of calcium ions (Ca2+) markedly falls, inhibiting exocytosis and potentially reducing adenosine release. However it has been observed that reducing extracellular Ca2+ can induce paradoxical neural activity and can also increase adenosine release. Here we have investigated adenosine signaling and release mechanisms that occur when extracellular Ca2+ is removed. Using electrophysiology and microelectrode biosensor measurements we have found that adenosine is directly released into the extracellular space by the removal of extracellular Ca2+ and controls the induced neural activity via A1 receptor-mediated membrane potential hyperpolarization. Following Ca2+ removal, adenosine is released via equilibrative nucleoside transporters (ENTs), which when blocked leads to hyper-excitation. We propose that sustained action potential firing following Ca2+ removal leads to hydrolysis of ATP and a build-up of intracellular adenosine which then effluxes into the extracellular space via ENTs.
Highlights
The purine adenosine is a potent neuromodulator involved in many physiological and pathological processes
This was followed by a recovery of the membrane potential back to a value close to that observed at rest, interrupted with short membrane potential depolarizations (∼3–6 mV, mean depolarization 5.4 ± 0.5 mV occurring at a frequency between 2 Hz and 5 Hz) and superimposed bursts of action potentials (Figure 1A as previously described in Konnerth et al, 1986; Bikson et al, 2002)
We have shown that adenosine plays a key feedback role in controlling activity in the hippocampus induced by a reduction in extracellular Ca2+ concentration
Summary
The purine adenosine is a potent neuromodulator involved in many physiological and pathological processes (reviewed in Dunwiddie and Masino, 2001; Sebastião and Ribeiro, 2009; Borea et al, 2016). There is evidence that adenosine can be released directly by exocytosis in the cerebellum (Klyuch et al, 2012). In the hippocampus, it appears that activity-dependent adenosine release occurs via a combination of different mechanisms which include exocytosis of ATP and transporter-mediated release (Wall and Dale, 2013)
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