Dopamine receptors and dopamine-sensitive adenylate cyclase in canine caudate nucleus

Sano, Kenji; Noshiro, Osamu; Katsuda, Kimio; Nishikori, Koji; Maeno, Hiroo

doi:10.1016/0006-2952(79)90408-8

Cited by 29 publications

(24 citation statements)

References 25 publications

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“…However, the dissociation constant is an equilibrium constant, so it should only be used for calculating the receptor occupancy when the duration of the DA signal is longer than the time needed to reach the equilibrium. As this is typically not the case for phasic DA signals, since the half-life time of receptors is longer (Burt et al, 1976; Sano et al, 1979; Maeno, 1982; Nishikori et al, 1980) than the timeframe of phasic signaling (Roitman et al, 2004), we developed a model which incorporates slow kinetics. When DA and one of its receptors are both present in a solution they constantly bind and unbind.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to the receptor concentration, the kinetic constants of the receptors are key parameters in our slow kinetics model. In an equilibrium measurement in the canine caudate nucleus the dissociation constant of low affinity DA binding sites, corresponding to D1 receptors (Maeno, 1982), has been measured as K D = 1.6 μM (Sano et al, 1979). However, when calculating K D (using Eq.…”

Section: Methodsmentioning

confidence: 99%

“…However, when calculating K D (using Eq. 8) from the measured kinetic constants (Sano et al, 1979) the value is . To be more easily comparable to other simulation works (Dreyer et al, 2010) and direct measurements (Richfield et al, 1989; Sano et al, 1979) we choose in our simulations.…”

Section: Methodsmentioning

confidence: 99%

“…However, this assumption holds only if the receptor kinetics are fast compared to the timescale of the DA signal, which is typically not the case. For instance, D1Rs and D2Rs unbind from DA with a half-life time of t 1/2 ≈ 80s (Burt et al, 1976; Sano et al, 1979; Maeno, 1982; Nishikori et al, 1980), much longer than phasic signals of a few seconds (Robinson et al, 2001; Schultz, 2007; Hamid et al, 2016). Moreover, the fraction of bound receptors might be a misleading measure for the effect of DA signals, since the abundances of D1R and D2R in the striatum are quite different.…”

Section: Introductionmentioning

confidence: 99%

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Abundance compensates kinetics: Similar effect of dopamine signals on D1 and D2 receptor populations

Hunger

Kumar

Schmidt

2018

Preprint

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The neuromodulator dopamine plays a key role in motivation, reward-related learning and normal motor function. The different affinity of striatal D1 and D2 dopamine receptor types has been argued to constrain the D1 and D2 signalling pathways to phasic and tonic dopamine signals, respectively. However, this view assumes that dopamine receptor kinetics are instantaneous so that the time courses of changes in dopamine concentration and changes in receptor occupation are basically identical. Here we developed a neurochemical model of dopamine receptor binding taking into account the different kinetics and abundance of D1 and D2 receptors in the striatum. Testing a large range of behaviorally-relevant dopamine signals, we found that the D1 and D2 dopamine receptor populations responded very similarly to tonic and phasic dopamine signals. Furthermore, due to slow unbinding rates, both receptor populations integrated dopamine signals over a timescale of minutes. Our model provides a description of how physiological dopamine signals translate into changes in dopamine receptor occupation in the striatum, and explains why dopamine ramps are an effective signal to occupy dopamine receptors. Overall, our model points to the importance of taking into account receptor kinetics for functional considerations of dopamine signalling. Significance statementCurrent models of basal ganglia function are often based on a distinction of two types of 1 dopamine receptors, D1 and D2, with low and high affinity, respectively. Thereby, phasic 2 dopamine signals are believed to mostly affect striatal neurons with D1 receptors, and tonic 3 dopamine signals are believed to mostly affect striatal neurons with D2 receptors. This view 4 does not take into account the rates for the binding and unbinding of dopamine to D1 and 5 D2 receptors. By incorporating these kinetics into a computational model we show that D1 6 and D2 receptors both respond to phasic and tonic dopamine signals. This has implications 7 for the processing of reward-related and motivational signals in the basal ganglia. 8 35 1989) leading to ≈ 40% of D2Rs being occupied at a baseline [DA] of 20nM . Due to their high 36 affinity, D2Rs can detect low amplitude, tonic increases/decreases in [DA]. However, as D2Rs 37 saturate at relatively low [DA] > 2 · K D2 D , and are therefore unable to detect high amplitude, 38 phasic increases in [DA]. This suggests that D1 and D2 type MSNs respond differently to 39 2 Hunger et al. Dopamine receptor abundance compensates kinetics phasic and tonic changes in [DA], solely because of the different affinities of D1Rs and D2Rs 40 (Schultz, 2007). However, this model neglects other factors relevant for receptor occupation 41 and is also incompatible with recent findings that D2R expressing MSNs can detect phasic 42 changes in [DA] (Marcott et al., 2014; Yapo et al., 2017). 43The affinity-based model assumes that the reaction equilibrium is reached instantaneously, 44 whereby the receptor binding affinity can be used to approximate the fraction of r...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Abundance compensates kinetics: Similar effect of dopamine signals on D1 and D2 receptor populations

Hunger

Kumar

Schmidt

2018

Preprint

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“…However, whether these subtypes represent entirely different DA receptor proteins or they are simply the same receptor protein in different conformational states remains to be determined. Solubilization, partial purification, and characterization of agonist and antagonist binding sites of DA-Rs have been achieved [Clement-Cormier and George, 1979;Titeler et al, 1978a;Sano et al, 1979a;Leysen, 1979;Clement-Cormier and Kendrick, 1980;Boyan-Salyers and Clement-Cormier, 1980;Suen et al, 1980;Davis et al, 1981;Lew et al, 19811. To fully elucidate the ligandreceptor interaction between DA agonists or antagonists and the binding sites and to further characterize these DA-binding sites in terms of the molecular weight, subunits, and amino acid sequences, it is necessary to purify each of the DA-binding sites to homogeneity.…”

Section: Introductionmentioning

confidence: 99%

A brain synaptic dopamine‐binding protein: Isolation and partial characterization

Moroi

Hsu

1984

J of Neuroscience Research

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A dopamine-binding protein (DABP) has been purified from the rat brain cortex to homogeneity. Solubilization of the DABP from the synaptosomal membranes (P2M) by cholic acid, subsequent agarose gel filtration of the cholic acid extract to separate phospholipids from the DABP, and lastly DA affinity chromatography successfully resulted in a purified DABP with approximately 0.006% yield in protein concentration and 0.03% yield in specific [3H]-DA binding. The specific [3H]-DA binding of the purified DABP was 117 fmol/mg protein/10 min with a 4.6-fold purification compared with the whole homogenate. The purified DABP had an Rf value of 0.67 on native disk polyacrylamide gel and it gave one single polypeptide subunit on the SDS gel with an Rf value of 0.63. The apparent molecular weight of this single subunit was estimated to be 34.5 kilodaltons. The elution patterns from either DA- or ADTN-affinity (2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene-affinity) columns indicated that this DABP had higher affinity for DA agonists than for DA antagonists. Photoaffinity labeling of [3H]-DA to this DABP in the P2M fraction and the specific [3H]-DA to the purified DABP demonstrated a nanomolar range affinity corresponding to either D2 or D3 receptors. These data suggested that the purified DABP could be related to either D2 or D3 receptors in the brain.

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Cyclic Nucleotide Metabolism

Bonnet

1983

Handbook of Neurochemistry

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Dopamine receptors and dopamine-sensitive adenylate cyclase in canine caudate nucleus

Cited by 29 publications

References 25 publications

Abundance compensates kinetics: Similar effect of dopamine signals on D1 and D2 receptor populations

Abundance compensates kinetics: Similar effect of dopamine signals on D1 and D2 receptor populations

A brain synaptic dopamine‐binding protein: Isolation and partial characterization

Cyclic Nucleotide Metabolism

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