Heteromerization of dopamine D2 receptors with dopamine D1 or D5 receptors generates intracellular calcium signaling by different mechanisms

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The repertoire of signal transduction pathways activated by dopamine in brain includes the increase of intracellular calcium. However the mechanism(s) by which dopamine activated this important second messenger system was/were unknown. Although we showed that activation of the D5 dopamine receptor increased calcium concentrations, the restricted anatomic distribution of this receptor made this unlikely to be the major mechanism in brain. We have identified novel heteromeric dopamine receptor complexes that are linked to calcium signaling. The calcium pathway activated through the D1–D2 receptor heteromer involved coupling to Gq, through phospholipase C and IP3 receptors to result in a rise in intracellular calcium. The calcium rise activated through the D2–D5 receptor heteromer involved a small rise in intracellular calcium through the Gq pathway that triggered a store-operated channel mediated influx of extracellular calcium. These novel receptor heteromeric complexes, for the first time, establish the link between dopamine action and rapid calcium signaling.

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.

References (64)

  • J.K. Seamans et al.

    The principal features and mechanisms of dopamine modulation in the prefrontal cortex

    Prog Neurobiol

    (2004)
  • E. Friedman et al.

    D1-like dopaminergic activation of phosphoinositide hydrolysis is independent of D1A dopamine receptors: evidence from D1A knockout mice

    Mol Pharmacol

    (1997)
  • D.M. Montague et al.

    Quantification of D1B(D5) receptors in dopamine D1A receptor-deficient mice

    Synapse

    (2001)
  • A. Mouri et al.

    Involvement of a dysfunctional dopamine-D1/N-methyl-d-aspartate-NR1 and Ca2+/calmodulin-dependent protein kinase II pathway in the impairment of latent learning in a model of schizophrenia induced by phencyclidine

    Mol Pharmacol

    (2007)
  • W.J. Rushlow et al.

    Antipsychotics affect multiple calcium calmodulin dependent proteins

    Neuroscience

    (2009)
  • S.M. Anderson et al.

    CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking

    Nat Neurosci

    (2008)
  • A.C. Kreitzer et al.

    Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models

    Nature

    (2007)
  • C. Missale et al.

    Dopamine receptors: from structure to function

    Physiol Rev

    (1998)
  • K.A. Neve et al.

    Dopamine receptor signaling

    J Recept Signal Transduct Res

    (2004)
  • R. Pivonello et al.

    Novel insights in dopamine receptor physiology

    Eur J Endocrinol

    (2007)
  • S.R. George et al.

    A novel dopamine receptor signaling unit in brain: heterooligomers of D1 and D2 dopamine receptors

    Sci World J

    (2007)
  • C.H. So et al.

    Calcium signaling by dopamine D5 receptor and D5–D2 receptor hetero-oligomers occurs by a mechanism distinct from that for dopamine D1–D2 receptor hetero-oligomers

    Mol Pharmacol

    (2009)
  • L.Q. Jin et al.

    SKF83959 selectively regulates phosphatidylinositol-linked D1 dopamine receptors in rat brain

    J Neurochem

    (2003)
  • A.S. Undie et al.

    Stimulation of a dopamine D1 receptor enhances inositol phosphates formation in rat brain

    J Pharmacol Exp Ther

    (1990)
  • N. Lezcano et al.

    D1/D5 dopamine receptors stimulate intracellular calcium release in primary cultures of neocortical and hippocampal neurons

    J Neurophysiol

    (2002)
  • T.S. Tang et al.

    Dopamine receptor-mediated Ca2+ signaling in striatal medium spiny neurons

    J Biol Chem

    (2004)
  • C.H. So et al.

    D1 and D2 dopamine receptors form heterooligomers and co-internalize after selective activation of either receptor

    Mol Pharmacol

    (2005)
  • M. Dziedzicka-Wasylewska et al.

    Fluorescence studies reveal heterodimerization of dopamine D1 and D2 receptors in the plasma membrane

    Biochemistry

    (2006)
  • D. Lee et al.

    Dopamine induces a biphasic modulation of hypothalamic ANF neurons: a ligand concentration-dependent effect involving D5 and D2 receptor interaction

    Mol Psychiatry

    (2000)
  • G.J. O'Sullivan et al.

    Ethological resolution of behavioural topography and D1-like versus D2-like agonist responses in congenic D5 dopamine receptor mutants: identification of D5:D2-like interactions

    Synapse

    (2005)
  • R.S. Ostrom et al.

    The evolving role of lipid rafts and caveolae in G protein-coupled receptor signaling: implications for molecular pharmacology

    Br J Pharmacol

    (2004)
  • P.A. Insel et al.

    Compartmentation of G-protein-coupled receptors and their signalling components in lipid rafts and caveolae

    Biochem Soc Trans

    (2005)
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