{"content"=>"Essential Control of the Function of the Striatopallidal Neuron by Pre-coupled Complexes of Adenosine A-Dopamine D Receptor Heterotetramers and Adenylyl Cyclase.", "sub"=>[{"content"=>"2A"}, {"content"=>"2"}]} (original) (raw)
Related papers
1992
A cDNA fragment homologous to other G protein-coupled receptors was isolated from rat brain using the PCR method and demonstrated to be abundantly expressed in striatum. Using this fragment as a probe, a 2.1 kb full-length cDNA was isolated from a rat striatal cDNA library. This cDNA encodes a protein of 410 amino acids and is highly homologous to previously isolated adenosine receptor cDNAs. Expression of this eDNA in COS cells revealed high affinity (K d = 38.6 nM) and saturable binding of the A. adenosine receptor-selective ligand [~H]CGS 21680. Agonist displacement profile of [3H]CGS 21680 binding was consistent with an adenosine receptor of the A e subtype (NECA > (R)-PIA > CPA > (S)-PIA). In situ hybridization demonstrated that rat A~ adenosine receptor mRNA was co-expressed in the same striatal neurons as D e dopamine receptor mRNA, and never co-expressed with striatal D l dopamine receptor mRNA. Several lines of evidence have previously suggested that dopamine-induced changes in motor behavior can be modulated by adenosine analogs acting at the A 2 subtype of adenosine receptor in the forebrain. The co-expression of D 2 dopamine and A 2 adenosine receptors in a subset of striatal cells provides an anatomical basis for dopaminergic-adenosinergic interactions on motor behavior.
Brain Research Reviews, 1998
An analysis at the network and membrane level has provided evidence that antagonistic interactions between adenosine A2A/dopamine D 2 and adenosine A~/dopamine D 1 receptors in the ventral and dorsal striatum are at least in part responsible for the motor stimulant effects of adenosine receptor antagonists like caffeine and for the motor depressant actions of adenosine receptor agonists. The results obtained in stably cotransfected cells also underline the hypothesis that the intramembrane A2A//D2 and A1//D1 receptor interactions represent functionally important mechanisms that may be the major mechanism for the demonstrated antagonistic AEA//D2 and A1/D 1 receptor interactions found in vivo in behavioural studies and in studies on in vivo microdialysis of the striopallidal and strioentopeduncular GABAergic pathways. A major mechanism for the direct intramembrane A 2A//D2 and A l/D1 receptor interactions may involve formation of AEA/D 2 and AI/D 1 heterodimers leading to allosteric changes that will alter the affinity as well as the G protein coupling and thus the efficacy to control the target proteins in the membranes. This is the first molecular network to cellular integration in the nerve cell membrane and may be well suited for a number of integrated tasks and can be performed in a short-time scale, in comparison with the very long-time scale observed when receptor heteroregulation involves phosphorylation or receptor resynthesis. Multiple receptor-receptor interactions within the membranes through formation of receptor clusters may lead to the storage of information within the membranes. Such molecular circuits can represent hidden layers within the membranes that substantially increase the computational potential of neuronal networks. These molecular circuits are biased and may therefore represent part of the molecular mechanism for the storage of memory traces (engrams) in the membranes.
Brain Research, 2010
The modulation of the striato-pallidal pathway by presynaptic adenosine A2a and dopamine D2 receptors has gained attention in the study of Parkinson's disease. Here, we analyzed the effect of presynaptic A2a receptors in the spiking activity of globus pallidus (GP) neurons recorded during electrical stimulation of the striato-pallidal pathway, in both sham and ipsilaterally dopamine-denervated rats. We found that intrapallidal blockade of A2a by 100 pMol KF-17383 in sham and lesioned rats did not modify the spiking rate of GP neurons. Local infusion of 100 pMol CGS-21680, an A2a agonist, did not change the spiking rate in sham rats, whereas the same concentration of NMDA strongly increased the firing frequency of all neurons tested. Moreover, in sham rats, local blockade of A2a receptors by 100 pMol KF-17383 suppressed the inhibition evoked by activation of the striato-pallidal pathway, while in dopaminedenervated rats the same dose of KF-17383 did not modify the inhibition. Our results show that the contribution of A2a receptors to the spiking control of GP by the striatopallidal pathway depends on the state of the dopaminergic system.
The vast majority of striatal neurons are GABAergic medium-sized spiny neurons. These cells receive glutamatergic input from the cortex, thalamus and limbic areas and dopaminergic input from the mesencephalon. Most relevant evidence indicates that dopamine D 1 receptors are located on striatonigral projection neurons, 5,7 and that adenosine A 2A receptors 4,12,14 and most dopamine D 2 receptors 5,7,14 are located on striatopallidal projection neurons (see, however, Refs 1 and 13). Here we have utilized regulation of the phosphorylation of dopamine-and cyclic AMPregulated phosphoprotein of mol. wt 32,000 (DARPP-32) to study the possible interactions among nigrostriatal dopaminergic neurons and the two classes of dopaminoceptive target neurons. We show that, in striatal slices, the D 2 receptor agonist, quinpirole, strongly inhibits the phosphorylation of DARPP-32 induced by either the D 1 receptor agonist, SKF 81297, or the A 2A receptor agonist, CGS 21680. Tetrodotoxin abolished the effect of quinpirole on the D 1 agonistinduced but not the A 2A agonist-induced phosphorylation of DARPP-32. These data indicate that: (i) adenosine A 2A and dopamine D 2 receptors interact within the same striatopallidal neurons, and (ii) D 2 receptors present on the striatopallidal neurons modulate the effects of D 1 receptors on the striatonigral neurons. Thus, a single neurotransmitter is capable of activating distinct classes of receptors on distinct populations of target neurons, which, in turn, interact with each other through intercellular communication. 1998 IBRO. Published by Elsevier Science Ltd.
Brain Research, 1992
We have previously fimnd, in striatal membrane preparations from young (2 months old) rats, that stimulation of adenosine A, receptors (with the selective ~,dcnosine A., agonist CGS 21680) increases the dissociation constants of high-(Kh) and low-affinity (K I) dopamine D: binding sites (labelled with the selective dopamine D., antagonist ['~lt]raclopride) without changing the proportion of high affinity binding sites (RI,). in the present study in striatal preparations from adult (6 months old) rats, it was found that in addition to the increase in both K h and K I values, stimulation of adenosine A, receptors is associated with an increase in R h. These results suggest that, in the adult rat, adenosine A: stimulation nlay inhibit the hehavioural effects induced by dopamine D, stinlulation both by decreasing the affinity and the transduction of dopamine D, receptors. We have :dso studied the i,ltramembrane A,-D, receptor interaction in an experimental model of Parkinson's disease, namely in rats will) Ii unilateral 6.Oll-dopamine-induced lesion of the nigro-striatal dopamine pathway. It was found that a unilateral dopamine denervation is llSSO(2iated with a higher density of striatal dopamine D z receptors in the order of 20%, without any change in their affinity compared with the unlcsioned neostriatum. Furthermore, the density (Bm,~ values) of dopamine D, receptors in the contralateral neostriatum was significantly higher (al'lollt 2()¢;) than in the sir)alum from naive animals. This finding suggests that an unilateral dopanline denervation also induces compensatory long-lasting changes of dopamine i), receptors in the contralateral neostrlalum, In addition to the heightened sensitivity to dopamin¢ anon)sis, it is known that the dopamine denervated sir)alum is there sensitive to adenosine antagonists like methylxanlhines. If the adenosine A,-dopamin¢ D: interaction is the main mechanism of action mediating the central effects of methylxanthines, the dopamine denervation might alst~ potentiate this interaction, i.¢., dopamine D,, receptors could t~e not only more sensitive to dopamin¢ hut also to adenosine A: receptor act)vat)tin. Our results support this hypothesis, since membrane preparations from the denervated neostriatum are more sensitive to the effect of COS 21{~81) on dopamine D 2 receptors. Thus a low dose of COS 21(~80 (3 nM), which is not effective in membrane preparations from the neostriatt, m of naive animals, is still effective in membranes from the denervated neostriatum. These results underline the potential antiparkinsonian activity of adenosine A, antagonists.