Adenosine. Adenosine is an endogenous purine nucleoside that is generated extracellularly from adenine nucleotides like ATP and intracellularly from 5'-AMP or S-adenosyl-homocysteine. Adenosine can be converted into inosine by adenosine deaminase or back into 5'-AMP by adenosine kinase (Figure 3). Adenosine kinase is important in regulation of the basal intracellular levels of adenosine, whereas adenosine deaminase lowers the increased adenosine that is generated during neuronal excitation. The normal concentration of adenosine in brain varies widely based on metabolic state, ranging between 25 and 250 nM in rat. Physiologic extracellular concentrations of adenosine in the brain are sufficient to generate sustained tonic activation of A1AR and A2AAR.
The transmembrane adenosine transporter maintains an equilibrium of adenosine concentration across cell membranes by passively (that is, independent of ATP or ionic gradients) transporting adenosine in either direction. Under normal conditions, adenosine kinase lowers intracellular adenosine concentrations, resulting in inward transport of adenosine from the extracellular space by transmembrane transporters. During pathologic states (for example, hypoxia and ischemia), intracellular adenosine concentrations may rise due to increased ATP hydrolysis in the cell; the transporterthen moves adenosine out of the cell. Transport of adenosine via a sodium gradient mechanism has also been proposed.
Adenosine (see Ventolin inhalers: use and care) is produced throughout the brain. Under physiologic conditions, adenosine functions primarily as a negative modulator of neuronal activity. Despite its significant effect on the physiology of central nervous system, adenosine does not meet the widely accepted standards used to define neurotransmitters. For instance, adenosine is not removed from the synapse by active re-uptake or stored in vesicles within neuronal terminal prior to release, and it is not released into synaptic cleft in an intracellular calcium-dependent manner upon neuronal firing. As a result, adenosine generally is categorized as a modulator of neurotransmission, and it exerts its functions through binding to G protein-coupled high-affinity adenosine receptors.
Figure 3. Adenosine synthesis and metabolism.
The transmembrane adenosine transporter maintains an equilibrium of adenosine concentration across cell membranes by passively (that is, independent of ATP or ionic gradients) transporting adenosine in either direction. Under normal conditions, adenosine kinase lowers intracellular adenosine concentrations, resulting in inward transport of adenosine from the extracellular space by transmembrane transporters. During pathologic states (for example, hypoxia and ischemia), intracellular adenosine concentrations may rise due to increased ATP hydrolysis in the cell; the transporterthen moves adenosine out of the cell. Transport of adenosine via a sodium gradient mechanism has also been proposed.
Adenosine (see Ventolin inhalers: use and care) is produced throughout the brain. Under physiologic conditions, adenosine functions primarily as a negative modulator of neuronal activity. Despite its significant effect on the physiology of central nervous system, adenosine does not meet the widely accepted standards used to define neurotransmitters. For instance, adenosine is not removed from the synapse by active re-uptake or stored in vesicles within neuronal terminal prior to release, and it is not released into synaptic cleft in an intracellular calcium-dependent manner upon neuronal firing. As a result, adenosine generally is categorized as a modulator of neurotransmission, and it exerts its functions through binding to G protein-coupled high-affinity adenosine receptors.
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