Heteromerization of dopamine D2 receptors with dopamine D1 or D5 receptors generates intracellular calcium signaling by different mechanisms
Introduction
Dopamine is involved in the regulation of various physiological functions including locomotion, behavior, learning, and emotion. In a variety of diseases, such as Alzheimer's disease, schizophrenia, Parkinson's disease, and drug addiction, the pathophysiology has been linked to dysfunctional dopaminergic signaling [1, 2, 3]. The genes for five dopamine receptors (D1R–D5R) have been cloned and the receptors shown to belong to the G-protein-coupled receptor (GPCR) superfamily, which based on their sequence homology, pharmacology, and the modulation of cyclic AMP, were divided into two major subclasses, the D1-like and D2-like receptors [1, 2]. D1-like receptors (D1R and D5R) activate, whereas D2-like receptors (D2R, D3R, and D4R) inhibit adenylyl cyclase (AC) activity, resulting in opposite modulation of cyclic AMP through Gs/olf or Gi/o proteins, respectively [2]. The modulation of this pathway and related proteins, protein kinase A (PKA), and DARPP32 (dopamine and PKA regulated protein) represents the most studied dopamine signaling pathway [4], but other signaling cascades have been reported, including the modulation of the Akt–GSK3 pathway [5] and the activation of the PAR4 signaling pathway [6]. We have reported a new calcium–CaMKII (calcium–calmodulin kinase) signaling pathway activated through heteromerization between D1R and D2R creating D1–D2 heteromers (reviewed in [7, 8]). We have also reported another heteromerization involving D2R and D5R, leading to the formation of D2–D5 heteromeric complexes [9•], which also signal via calcium. These novel pathways, for the first time, show a link between dopamine action and rapid calcium signaling. We will describe these two heteromeric receptor complexes and their signaling, and discuss their differences along with their respective putative physiological relevance.
Section snippets
D1–D2 heteromers and intracellular calcium mobilization
Evidence of a D1-like receptor activating IP3 production and/or increasing intracellular calcium has been described to occur in slices from different brain regions, such as striatum, hippocampus, and cortex [10, 11, 12]. It was also shown in striatal neurons in culture that the activation of a D1-like receptor resulted in a rise in intracellular calcium, which was mobilized through both extracellular influx and from intracellular compartments [13]. However, no such effects were observed when
D2–D5 heteromers and calcium signaling
Owing to the high sequence homology (∼80%) between the two dopamine D1-like class receptors, D1R and D5R, and the absence of specific agonists and antagonists able to discriminate between these two receptors, we postulated that the occurrence of cooperativity and synergism between D2-like and D1-like receptors may also involve the D2R and D5R pair. We therefore investigated the possibility of heteromerization between these two receptors. FRET analysis showed that D2R and D5R formed heteromeric
Differences in calcium signaling between D1–D2 and D2–D5 receptor heteromers
It is interesting to note that by forming heteromers with the same receptor, namely D2R, two related receptors, D1R and D5R, with very similar pharmacological properties, showed different patterns of dopamine-induced calcium regulation. These two different effects, when considered together with the known signaling of the receptor homooligomers through the modulation of adenylyl cyclase and cAMP, identify multiple pathways of signal transduction by dopamine (Figure 1). The effects of receptor
Physiological relevance
It is well established that D1-like and D2-like receptors can mediate opposing as well as synergistic effects depending on cellular location, the brain region involved (reviewed in [50•]) and also on the local dopamine concentrations [51]. For example, it has been reported that dopamine attenuates glutamatergic input in the nucleus accumbens through D1-like receptors, whereas, no direct effects on postsynaptic glutamatergic NMDARs and AMPARs were observed in the dorsal striatum. In the latter
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The work on dopamine receptors in our laboratory is supported by a grant from the National Institute on Drug Abuse. SRG holds the Canada Research Chair in Molecular Neuroscience.
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