Hi There

Both D1 and D2 dopamine (DA) receptors have opposing actions on intracellular signaling molecules and results in varied physiological effects; however, it is not clear how D1 versus D2 signaling activates. Jeremy K Seamens groups used in vitro patch-clamp recordings show DA concentration is critical determinant of D1 versus D2 signaling in prefrontal cortex.

Here is the reference...which you can get broad picture, why they have opposing effects

Title: Mechanisms Underlying Differential D1 versus D2 Dopamine Receptor Regulation of Inhibition in Prefrontal Cortex

Heather Trantham-Davidson, Laurence C. Neely, Antonieta Lavin, and Jeremy K. Seamans, The Journal of Neuroscience, November 24, 2004 • 24(47):10652–10659.

RKG

Thanks，Rajendra Gangalum. The nice paper by Heather Trantham-Davidson et al. provides a broad picture that lower [DA] evokes D1 and higher [DA] evokes both D1 and D2. But when I try write a function of proportion of activated DA receptor over [DA], I want to know more details about the dependence on concentration, for example, the lowest concentration at which the receptors become active, the concentration at which half receptors become activated.

Thanks again.

Why not looking at this nice modeling paper?

J Neurosci. 2010 Oct 20;30(42):14273-83.

Influence of phasic and tonic dopamine release on receptor activation.

Thanks Nicolas Gervasi. There is somewhat contradiction between two papers. One showed that lower concentration favors D1,higher concentration favors both D1 and D2. However, another paper chose Kd =1 uM for D1 and Kd=10nM for D2. I guess that the later paper(J Neurosci. 2010 Oct 20;30(42):14273-83.) thinks that D1 operates at low affinity state.

Dear all

The paper J Neurosci. 2010 Oct 20;30(42):14273-83 assumes that D1 operates is low affinity state and that D2 operates in a high affinity state. The other paper addres signals in prefrontal cortex where their roles seem to be the opposite. (But I haven't worked in Prefrontal Ctx, so I dont know the literature there very well.)

The assumption of D2 high and D1 low in striatum is in agreement with Bertran-Gonzales, J. Neuroscience, May 28, 2008 • 28(22):5671–5685. and seems to be the consensus for DA receptors in nucleus accumbens and striatum (for example D1 but not D2 receptors are strongly activated by cocaine). But, to my knowledge, the smoking gun is missing. I have not found a direct measurement linking the high affinity state to be only the biologically relevant state: in in vitro studies mostly indicate both high and low affinity states of both D1 and D2.

In the model in J Neurosci 2010, post synaptic receptors are only described by their affinity, so results described as 'D2' will also apply for 'Low affinity state D2'. And vice versa: results described for 'D1' may also apply to 'D2 high'. (In my later paper, JK Dreyer, J. Neurophys, 2013: I just write High or low affinity receptors instead...)

So in conclusion: Be careful! The role of D1 and D2 may depend on the brain region you look. And keep an open mind! Most of what we know about the roles of D1 and D2 receptors is interpretations based on pharmacology, drug abuse, and Parkinsons disease which may not reflect the 'natural' signaling of the receptors very well.

good luck,

Jakob Kisbye Dreyer, Copenhagen

Extracellular dopamine certainly has differential effects on the D1 and D2 receptors, at least in striatum. However, the apparent efficacy appears to be quite effector-dependent ([1] could be seen by comparing Marcott et al. Neuron. 2014 Oct 1;84(1):164-176. from older biochemical reports on receptor affinity and cAMP measurements etc. for D2; [2] comparison of figure 5A and F in a modeling study, Nair et al. J Neurosci. 2015 Oct 14;35(41):14017-30.). Additionally, the receptor affinity values could be substantially different from EC50 values of downstream signaling, which may be a more relevant parameter in several scenario (Schoffelmeer et al. Synapse. 1994 Jul;17(3):190-5.). To increase the complexity, these values also depend on experimental preparation and there is a view that the measurements in membrane preparations etc may not reflect the actual scenario within intact neurons ([1] alluded to in Marcott et al. Neuron. 2014 Oct 1;84(1):164-176). We have recently characterized the efficacy of D1 and D2 receptors on downstream cAMP and PKA changes in intact striatal MSNs in mouse brain slices using FRET-based biosensors. The EC50 value for dopamine on D1-dependent cAMP appears to be quite consistent with previous reports (around 1uM). Whereas the EC50 value for dopamine on D2-dependent cAMP is quite different from what we initially expected. It was in the lower sub-micromolar range rather than being in nanomolar range. You could find more details in [Yapo et al. Detection of phasic dopamine by D1 and D2 striatal medium spiny neurons. J Physiol. 2017].

Best regards,

AnuNair

Anu G. Nair thanks for the nice summary of great information.

Regarding EC50 values for dopamine, could you provide some references?

Siripuram Vijay Kumar You could take a look at (Cumming P, Synapse. 2011, 65(9):892-909) for a review of EC50 on receptor activity. And (Yapo et al., J Physiol. 2017, 595(24):7451-7475) for EC50 on dopamine-dependent striatal cAMP signaling.