uptake” (via GAT proteins). β-Alanine binding sites have been identified throughout the
hippocampus, other limbic structures, and the neocortex. Finally (of great importance), an
active transport shuttle capable of transporting β-alanine and related analogs across the
blood–brain barrier has been identified. Such a “beta-shuttle” may permit β-amino acid
analogs to gain access to the CNS via active uptake rather than passive diffusion.
4.13 PURINERGIC NEUROMODULATION AND THE
ADENOSINE RECEPTORS
Purines have numerous biochemical functions: they are the building blocks of nucleic
acids, the energy transducers ATP and GTP, and the second messenger cAMP. They
have also been known to have other direct physiological functions in bronchial
constriction, in vasodilatation, and in inhibition of platelet aggregation and of central
neuronal firing. Owing to this widespread importance, the existence of purinergic
receptors (“P” receptors) has been speculated upon for many years. Originally, it was
thought that P receptors could bind only purines; however, it was later realized that
a subpopulation of purine receptors could also bind pyrimidines. The major purine
bases found in nucleotides are adenine, guanine, hypoxanthine, and xanthine; the major
pyrimidine bases found in nucleotides are cytosine, thymine, and uracil. Of the com-
pounds active at purinergic receptors, adenosine is the most noteworthy. Adenosine has
been found in numerous synapses and, in view of its bewildering multitude of actions,
has been called the “most mysterious neuromodulator.” Intensive research has shed
some light on purinergic activity that is defined as neuromodulation rather than neuro-
transmission, even though adenosine receptors are reasonably well elucidated.
Adenosine (4.238) is not a classical neurotransmitter because it is not stored in neuronal
synaptic granules or released in quanta.
Purinergic receptors are subdivided into two main groups, the P 1 and the P 2 receptors.
The P 1 purinergic receptor is further subdivided into four types of adenosine receptors:
A 1 ,A2A,A2B, and A 3. All four of these belong to the superfamily of receptors that signal
via G-proteins and contain seven hydrophobic transmembrane-spanning segments. To
date, eleven subtypes of P 2 receptors have been identified: P2x1–7,P2y1,P2y2,P2y4,P2y6. The
P2xreceptors are coupled to ligand-gated channels; the P2yreceptors are G-protein cou-
pled. These various receptors have been cloned from mammalian species.
Purines act both pre- and postsynaptically. Adenosine inhibits the release of NE and
ACh in autonomic neuronal terminals, and both adenosine and ATP function as pre- and
NEUROTRANSMITTERS AND THEIR RECEPTORS 297