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AMP-activated protein kinase slows D2 dopamine autoreceptor desensitization in substantia nigra neurons.

ABSTRACT: Dopamine neurons in the substantia nigra zona compacta (SNC) are well known to express D2 receptors. When dopamine is released from somatodendritic sites, activation of D2 autoreceptors suppresses dopamine neuronal activity through activation of G protein-coupled K+ channels. AMP-activated protein kinase (AMPK) is a master enzyme that acts in somatic tissues to suppress energy expenditure and encourage energy production. We hypothesize that AMPK may also conserve energy in central neurons by reducing desensitization of D2 autoreceptors. We used whole-cell patch-clamp recordings to study the effects of AMPK activators and inhibitors on D2 autoreceptor-mediated current in SNC neurons in midbrain slices from rat pups (11-23 days post-natal). Slices were superfused with 100??M dopamine or 30??M quinpirole for 25?min, which evoked outward currents that decayed slowly over time. Although the AMPK activators A769662 and ZLN024 significantly slowed rundown of dopamine-evoked current, slowing of quinpirole-evoked current required the presence of a D1-like agonist (SKF38393). Moreover, the D1-like agonist also slowed the rundown of quinpirole-induced current even in the absence of an AMPK activator. Pharmacological antagonist experiments showed that the D1-like agonist effect required activation of either protein kinase A (PKA) or exchange protein directly activated by cAMP 2 (Epac2) pathways. In contrast, the effect of AMPK on rundown of current evoked by quinpirole plus SKF38393 required PKA but not Epac2. We conclude that AMPK slows D2 autoreceptor desensitization by augmenting the effect of D1-like receptors.

SUBMITTER: Yang W

PROVIDER: S-EPMC6745265 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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AMP-activated protein kinase slows D2 dopamine autoreceptor desensitization in substantia nigra neurons.

Yang Wei W Munhall Adam C AC Johnson Steven W SW

Neuropharmacology 20190710

Dopamine neurons in the substantia nigra zona compacta (SNC) are well known to express D2 receptors. When dopamine is released from somatodendritic sites, activation of D2 autoreceptors suppresses dopamine neuronal activity through activation of G protein-coupled K<sup>+</sup> channels. AMP-activated protein kinase (AMPK) is a master enzyme that acts in somatic tissues to suppress energy expenditure and encourage energy production. We hypothesize that AMPK may also conserve energy in central neu ...[more]

PMID: 31301335

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Project description:Dopamine midbrain neurons within the substantia nigra are particularly prone to degeneration in Parkinson's disease. Their selective loss causes the major motor symptoms of Parkinson's disease, but the causes for the high vulnerability of SN DA neurons, compared to neighbouring, more resistant ventral tegmental area dopamine neurons, are still unclear. Consequently, there is still no cure available for Parkinson's disease. Current therapies compensate the progressive loss of dopamine by administering its precursor l-DOPA and/or dopamine D2-receptor agonists. D2-autoreceptors and Cav1.3-containing L-type Ca(2+) channels both contribute to Parkinson's disease pathology. L-type Ca(2+) channel blockers protect SN DA neurons from degeneration in Parkinson's disease and its mouse models, and they are in clinical trials for neuroprotective Parkinson's disease therapy. However, their physiological functions in SN DA neurons remain unclear. D2-autoreceptors tune firing rates and dopamine release of SN DA neurons in a negative feedback loop through activation of G-protein coupled potassium channels (GIRK2, or KCNJ6). Mature SN DA neurons display prominent, non-desensitizing somatodendritic D2-autoreceptor responses that show pronounced desensitization in PARK-gene Parkinson's disease mouse models. We analysed surviving human SN DA neurons from patients with Parkinson's disease and from controls, and detected elevated messenger RNA levels of D2-autoreceptors and GIRK2 in Parkinson's disease. By electrophysiological analysis of postnatal juvenile and adult mouse SN DA neurons in in vitro brain-slices, we observed that D2-autoreceptor desensitization is reduced with postnatal maturation. Furthermore, a transient high-dopamine state in vivo, caused by one injection of either l-DOPA or cocaine, induced adult-like, non-desensitizing D2-autoreceptor responses, selectively in juvenile SN DA neurons, but not ventral tegmental area dopamine neurons. With pharmacological and genetic tools, we identified that the expression of this sensitized D2-autoreceptor phenotype required Cav1.3 L-type Ca(2+) channel activity, internal Ca(2+), and the interaction of the neuronal calcium sensor NCS-1 with D2-autoreceptors. Thus, we identified a first physiological function of Cav1.3 L-type Ca(2+) channels in SN DA neurons for homeostatic modulation of their D2-autoreceptor responses. L-type Ca(2+) channel activity however, was not important for pacemaker activity of mouse SN DA neurons. Furthermore, we detected elevated substantia nigra dopamine messenger RNA levels of NCS-1 (but not Cav1.2 or Cav1.3) after cocaine in mice, as well as in remaining human SN DA neurons in Parkinson's disease. Thus, our findings provide a novel homeostatic functional link in SN DA neurons between Cav1.3- L-type-Ca(2+) channels and D2-autoreceptor activity, controlled by NCS-1, and indicate that this adaptive signalling network (Cav1.3/NCS-1/D2/GIRK2) is also active in human SN DA neurons, and contributes to Parkinson's disease pathology. As it is accessible to pharmacological modulation, it provides a novel promising target for tuning substantia nigra dopamine neuron activity, and their vulnerability to degeneration.

Dataset Information

AMP-activated protein kinase slows D2 dopamine autoreceptor desensitization in substantia nigra neurons.

Publications

AMP-activated protein kinase slows D2 dopamine autoreceptor desensitization in substantia nigra neurons.

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