Distinct regulation of dopamine D2S and D2L autoreceptor signaling by calcium

Abstract

D2 autoreceptors regulate dopamine release throughout the brain. Two isoforms of the D2 receptor, D2S and D2L, are expressed in midbrain dopamine neurons. Differential roles of these isoforms as autoreceptors are poorly understood. By virally expressing the isoforms in dopamine neurons of D2 receptor knockout mice, this study assessed the calcium-dependence and drug-induced plasticity of D2S and D2L receptor-dependent G protein-coupled inwardly rectifying potassium (GIRK) currents. The results reveal that D2S, but not D2L receptors, exhibited calcium-dependent desensitization similar to that exhibited by endogenous autoreceptors. Two pathways of calcium signaling that regulated D2 autoreceptor-dependent GIRK signaling were identified, which distinctly affected desensitization and the magnitude of D2S and D2L receptor-dependent GIRK currents. Previous in vivo cocaine exposure removed calcium-dependent D2 autoreceptor desensitization in wild type, but not D2S-only mice. Thus, expression of D2S as the exclusive autoreceptor was insufficient for cocaine-induced plasticity, implying a functional role for the co-expression of D2S and D2L autoreceptors.DOI: http://dx.doi.org/10.7554/eLife.09358.001

Calcium Release from Stores Inhibits GIRK

“…This could be because the GIRK was already partially inhibited by the resting level of calcium (between ~115 and ~406 nM), as has been reported (Gantz et al, 2015b). On average, GIRK currents achieved with the same concentration of baclofen were ~30% smaller with caged-Ca 2+ in the pipette than with caged-IP 3 , likely occluding further calcium inhibition and minimizing the apparent effect of photolytic release of calcium.…”

“…Previous work has shown that GABA B and D2 receptors have differential sensitivity to calcium. Resting cytosolic calcium levels play a central role in the desensitization and long-term depression of the dopamine D2 receptor, but not the GABA B receptor (Beckstead and Williams, 2007; Gantz et al, 2015b). Increasing cytosolic calcium decreased peak GABA B R-, but not peak D2R-, mediated GIRK currents (Gantz et al, 2015b).…”

“…D2 receptors are also localized in close proximity to the calcium channel Ca v 1.3 (Dragicevic et al, 2014). Furthermore, depleting calcium stores or inhibiting calcium entry through the L-type voltage gated calcium channel increased the amplitude of a D2R-medaited GIRK current in wild type mice (Gantz et al, 2015b). Given the results of the present study in light of these results, it is possible that D2 receptor mediated GIRK currents at baseline are nearly maximally inhibited by calcium entry through Ca v 1.3, IP 3 receptors, and/or resting calcium levels.…”

“…Finally, calcium buffering and manipulations of the resting level of free calcium modulates the GIRK conductance activated by both D2 and GABA B receptors in that strong calcium buffering with BAPTA (10 mM) results in a larger GIRK currents (Beckstead and Williams, 2007; Gantz et al, 2015b). In addition the regulation of GIRK conductance by calcium is modulated following treatment of animals with psychostimulants.…”

“…In addition the regulation of GIRK conductance by calcium is modulated following treatment of animals with psychostimulants. The calcium-dependent inhibition of GIRK is augmented following treatment of animals with cocaine (Arora et al, 2011; Gantz et al, 2015b) and animals that self-administered methamphetamine (Sharpe et al, 2014). The mechanisms underlying these observation may differ in that there was no receptor dependence in animals that self-administered methamphetamine (Sharpe et al, 2014) whereas the present results indicate that the GABA B -induced currents are more susceptible to the calcium dependent regulation.…”