Dopamine receptor: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References
Gene name - Dopamine 1-like receptor 1

Synonyms - dDA1, Dopamine receptor, DopR

Cytological map position-88A10-88A12

Function - receptor

Keywords - behavior, mediation of aversive and appetitive Pavlovian conditioning

Symbol - Dop1R1

FlyBase ID: FBgn0011582

Genetic map position - 3R: 10,003,005..10,040,409 [-]

Classification - G-protein coupled receptor

Cellular location - transmembrane



NCBI links: Precomputed BLAST | EntrezGene | UniGene | HomoloGene | PubMed articles

Recent literature
Pitmon, E., Stephens, G., Parkhurst, S. J., Wolf, F. W., Kehne, G., Taylor, M. and Lebestky, T. (2016). The D1 Family Dopamine Receptor, DopR, potentiates hindleg grooming behavior in Drosophila. Genes Brain Behav [Epub ahead of print]. PubMed ID: 26749475
Summary:
Drosophila groom away debris and pathogens from the body using their legs in a stereotyped sequence of innate motor behaviors. This study investigated one aspect of the grooming repertoire by characterizing the D1 family dopamine receptor DopR. Removal of DopR results in decreased hindleg grooming, as substantiated by quantitation of dye remaining on mutant and RNAi animals versus controls and direct scoring of behavioral events. These data are also supported by pharmacological results that D1 receptor agonists fail to potentiate grooming behaviors in headless DopR flies. DopR protein is broadly expressed in the neuropil of the thoracic ganglion and overlaps with TH-positive dopaminergic neurons. Broad neuronal expression of Dopamine Receptor in mutant animals restored normal grooming behaviors. These data provide evidence for the role of DopR in potentiating hindleg grooming behaviors in the thoracic ganglion of adult Drosophila. This is a remarkable juxtaposition to the considerable role of D1 family dopamine receptors in rodent grooming, and future investigations of evolutionary relationships of circuitry may be warranted.

Zhang, Y., Guo, J., Guo, A. and Li, Y. (2016). Nicotine-induced acute hyperactivity is mediated by dopaminergic system in a sexually dimorphic manner. Neuroscience [Epub ahead of print]. PubMed ID: 27365175
Summary:
Short-term exposure to nicotine induces positive effects in mice, monkeys and humans, including mild euphoria, hyperactivity, and enhanced cognition.Using a video recording system, this study found that acute nicotine administration induces locomotor hyperactivity in Drosophila. Suppressing dopaminergic neurons or down-regulating Dopamine 1-like receptor (DopR) abolishes this acute nicotine response, but surprisingly, does so only in male flies. Using a GFP reconstitution across synaptic partners (GRASP) approach, dopaminergic neurons were shown to possess potential synaptic connections with acetylcholinergic neurons in wide regions of the brain. Furthermore, dopaminergic neurons are widely activated upon nicotine perfusion in both sexes, while the response curve differs significantly between the sexes. Moreover, knockdown of the β1 nicotine acetylcholine receptor (nAChR) in dopaminergic neurons abolishes the acute nicotine response only in male flies, while panneural knock-down occurs in both sexes. Taken together, these results reveal that in fruit flies, dopaminergic neurons mediate nicotine-induced acute locomotor hyperactivity in a sexually dimorphic manner, and Drosophila β1 nAChR subunit plays a crucial role in this nicotine response.
Jiang, Y., Pitmon, E., Berry, J., Wolf, F. W., McKenzie, Z. and Lebestky, T. J. (2016). A genetic screen to assess Dopamine receptor (DopR1) dependent sleep regulation in Drosophila. G3 (Bethesda) [Epub ahead of print]. PubMed ID: 27760793
Summary:
Sleep is an essential behavioral state of rest that is regulated by homeostatic drives to ensure a balance of sleep and activity, as well as independent arousal mechanisms in the central brain. Dopamine has been identified as a critical regulator of both sleep behavior and arousal. This study presents results of a genetic screen that selectively restored the Dopamine Receptor (DopR/DopR1/dumb) to specific neuroanatomical regions of the adult Drosophila brain to assess requirements for DopR in sleep behavior. Subsets of the mushroom body were identified that utilize DopR in daytime sleep regulation. These data are supported by multiple examples of spatially restricted genetic rescue data in discrete circuits of the mushroom body, as well as immunohistochemistry that corroborates the localization of DopR protein within mushroom body circuits. Independent loss of function data using an inducible RNAi construct in the same specific circuits also supports a requirement for DopR in daytime sleep. Additional circuit activation of discrete DopR+ mushroom body neurons also suggests roles for these subpopulations in sleep behavior. These conclusions support a new separable function for DopR in daytime sleep regulation within the mushroom body. This daytime regulation is independent of the known role of DopR in nighttime sleep, which is regulated within the Fan Shaped Body. This study provides new neuroanatomical loci for exploration of dopaminergic sleep functions in Drosophila, and expands understanding of sleep regulation during the day versus night.
Lim, J., Fernandez, A. I., Hinojos, S. J., Aranda, G. P., James, J., Seong, C. S. and Han, K. A. (2017). The mushroom body D1 dopamine receptor controls innate courtship drive. Genes Brain Behav [Epub ahead of print]. PubMed ID: 28902472
Summary:

Mating is critical for species survival and is profoundly regulated by neuromodulators and neurohormones to accommodate internal states and external factors. To identify the underlying neuromodulatory mechanisms, this study investigated the roles of dopamine receptors in various aspects of courtship behavior in Drosophila. The D1 dopamine receptor dDA1 regulates courtship drive in naive males. The wild-type naive males actively courted females regardless their appearance or mating status. On the contrary, the dDA1 mutant (dumb) males exhibited substantially reduced courtship toward less appealing females including decapitated, leg-less and mated females. The dumb male's reduced courtship activity was due to delay in courtship initiation and prolonged intervals between courtship bouts. The dampened courtship drive of dumb males was rescued by reinstated dDA1 expression in the mushroom body α/&beta& and γ neurons but not α/β or γ neurons alone, which is distinct from the previously characterized dDA1 functions in experience-dependent courtship or other learning and memory processes. It was also found that the dopamine receptors dDA1, DAMB and dD2R are dispensable for associative memory formation and short-term memory of conditioned courtship, thus courtship motivation and associative courtship learning and memory are regulated by distinct neuromodulatory mechanisms. Taken together, this study narrows the gap in the knowledge of the mechanism that dopamine regulates male courtship behavior (Lim, 2017).


BIOLOGICAL OVERVIEW

Drosophila has robust behavioral plasticity to avoid or prefer the odor that predicts punishment or food reward, respectively. Both types of plasticity are mediated by the mushroom body (MB) neurons in the brain, in which various signaling molecules play crucial roles. However, important yet unresolved molecules are the receptors that initiate aversive or appetitive learning cascades in the MB. D1 dopamine receptor dDA1 (FlyBase name: Dopamine receptor) has been shown to be highly enriched in the MB neuropil. This study demonstrates that dDA1 is a key receptor that mediates both aversive and appetitive learning in pavlovian olfactory conditioning. Two mutants, dumb1 and dumb2, have abnormal dDA1 expression. When trained with the same conditioned stimuli, both dumb alleles showed negligible learning in electric shock-mediated conditioning while they exhibited moderately impaired learning in sugar-mediated conditioning. These phenotypes are not attributable to anomalous sensory modalities of dumb mutants because their olfactory acuity, shock reactivity, and sugar preference are comparable to those of control lines. Remarkably, the dumb mutant's impaired performance in both paradigms is fully rescued by reinstating dDA1 expression in the same subset of MB neurons, indicating the critical roles of the MB dDA1 in aversive as well as appetitive learning. Previous studies using dopamine receptor antagonists implicate the involvement of D1/D5 receptors in various pavlovian conditioning tasks in mammals; however, these have not been supported by the studies of D1- or D5-deficient animals. The findings described in this study here unambiguously clarify the critical roles of D1 dopamine receptor in aversive and appetitive pavlovian conditioning (Kim, 2007b).

Pavlovian (classical) olfactory conditioning in Drosophila tests the animal's ability to learn and remember the odor [conditioned stimulus (CS)] associated with diverse unconditioned stimuli (US) and is instrumental in investigating the neural and cellular mechanisms underlying distinct learning and memory processes. When subjected to concurrent odor (CS+) and electric shock (aversive US) presentation, flies learn to avoid the CS+ odor in the absence of shock. Conversely, flies learn to prefer the CS+ odor after concurrent odor (CS+) and sugar (appetitive US) exposure. Thus, the same CS+ triggers either avoidance or preference behavior depending on previous experience of the flies. Several key questions arise regarding the underlying mechanisms. Specifically, are common or separate neural systems required for aversive versus appetitive learning and memory? What are the critical molecular and cellular events that distinguish reward versus punishment information (Kim, 2007b)?

Two key components are essential for both aversive and appetitive conditioning. One component is the cAMP signaling pathway. Flies defective in cAMP metabolism, such as dunce (cAMP-specific phosphodiesterase) and rutabaga [rut; calcium/calmodulin (CaM)-dependent adenylyl cyclase (AC)], or flies with altered activities of cAMP effectors Protein kinase A and dCREB2 are impaired in learning and/or memory in aversive conditioning. Likewise, appetitive conditioning requires cAMP because rut mutants display poor learning. The other component is the mushroom body (MB) brain structure. Flies with ablated MB structures or functions are completely defective in aversive learning. Moreover, synaptic output of different MB lobes is involved in memory formation or retrieval in aversive and appetitive conditioning. These indicate the MB as a central neural substrate for olfactory learning and memory. This poses a fundamental question regarding the neuromodulators and their receptors that initiate the cAMP cascade in the MB for aversive and appetitive learning and their memories (Kim, 2007b).

The neuromodulators that are crucial for olfactory conditioning and activate cAMP increases are dopamine and octopamine (see Tyramine β hydroxylase). Previous studies of Drosophila larvae and adults show that dopaminergic neuronal activities are essential for aversive, but not for appetitive, learning, whereas octopamine or octopaminergic neuronal activities are necessary only for appetitive learning (Schwaerzel, 2003; Schroll, 2006). Consistently, the activities of dopaminergic neurons projecting to the MB are mildly increased by odor stimuli and strongly by electric shock (Riemensperger, 2005). Moreover, duration of their activities is prolonged when the CS+ odor is presented, suggesting the role of dopamine neurons in US prediction. However, it is yet unknown whether dopamine directly activates the MB for aversive learning. To uncover the signal(s) activating the learning and memory cascade, three receptors have been identifed that are highly enriched in the MB and increase cAMP levels, and they are two dopamine receptors, dDA1 and DAMB, and an octopamine receptor, OAMB (Han, 1996; Han, 1998; Kim, 2003). This study shows that dDA1 is required in the MB for aversive and appetitive learning (Kim, 2007b).

Previous research on olfactory conditioning in Drosophila has primarily focused on the intracellular components, many of which are involved in learning and/or memory processes in the MB. Although those studies have revealed important insights, the receptors that initiate signaling cascades into motion in the MB are unknown. The findings presented here provide the first demonstration of a MB receptor essential for aversive learning. The role of dDA1 in this behavioral plasticity is physiological, rather than developmental. This is consistent with the observations that synaptic output of dopaminergic neurons is necessary during training (Schwaerzel, 2003), and the learning phenotype of rut mutants is rescued by the restricted expression of rut-AC, a potential dDA1 effector, in the adult MB (McGuire, 2003; Mao, 2004). Moreover, the dopaminergic processes projecting to the MB gamma lobe strongly respond to electric shock (US) and show altered activities after CS+ exposure (Riemensperger, 2005). Together, these strongly implicate dDA1 as a receptor conveying aversive US information in the MB lobes for memory formation (Kim, 2007b).

Two additional neuromodulator systems are previously implicated in aversive olfactory conditioning in Drosophila. One neuromodulator system is the glutamate NMDA receptor composed of dNR1 and dNR2 subunits. Flies with decreased dNR1 expression show diminished performance in aversive conditioning. Although dNR1 in the MB is crucial for anesthesia-resistant and midterm memories, dNR1-dependent learning occurs outside of the MB. Another putative modulator involved in olfactory learning is Amn, which has sequence homology with mammalian neuropeptide PACAP. Although amn mutants are mostly defective in midterm memory, they are mildly impaired in learning when BA is used as CS+ and learning of BA depends on synaptic output of Amn-expressing DPM neurons projecting to the MB lobes. Thus, it has been suggested that putative amn-encoded neuropeptides, by binding to their receptor(s) in the MB neuropil, may mediate memory formation; however, the predicted Amn neuropeptides or their receptors remain unidentified. Therefore, dDA1 represents the only MB receptor identified to date that is essential for aversive learning. Notably, dumb mutants, similar to MB-less flies, show negligible learning. This indicates that the MB neurons absolutely require dDA1 for aversive memory formation (Kim, 2007b).

The data presented in this study demonstrate the crucial role of dDA1 in sugar-mediated olfactory learning as well. Interestingly, dumb mutants have diminished, yet significant, performance scores, implicating an additional receptor(s) for this type of learning. Indeed, tßh mutants lacking octopamine show severe impairment in appetitive conditioning, which is rescued by feeding octopamine before, but not after, training (Schwaerzel, 2003). Thus, octopamine represents another neuromodulator crucial for appetitive learning. Because the MB is a primary neural substrate for appetitive conditioning, reward memory formation is likely mediated by dDA1 and an octopamine receptor(s) in the MB (Kim, 2007b).

The previous study of TH-GAL4/UAS-Shits flies, in which endocytosis of the dopamine neurons expressing TH-GAL4 can be temporally controlled by dominant-negative dynamin Shits, suggests that dopamine is not involved in appetitive conditioning (Schwaerzel, 2003; Kim, 2007a). This is contrary to the learning phenotype of D1 dopamine receptor mutants dumb. Nonetheless, the discrepancy may be reconciled by several reasonable possibilities: (1) TH-GAL4 used in the previous study to drive Shits may not be expressed, or expressed at low levels, in a subset of the dopamine neurons critical for appetitive learning; (2) dopamine neuronal output conveying sugar information may not be completely inhibited by Shits; (3) dopamine crucial for appetitive learning may be secreted by a dynamin-independent pathway. These possibilities may be tested by investigating pale mutants that are unable to synthesize dopamine; however, such flies die during development because of an essential role of dopamine in cuticle formation (Budnik, 1987). Future studies on conditional pale mutants should help resolve this issue (Kim, 2007b).

dDA1 expression driven by MB247-GAL4 fully rescues the learning phenotypes of dumb mutants in electric shock- as well as sugar-mediated conditioning. This indicates that appetitive and aversive memory formations are mediated by dDA1 in the same subset of the MB neurons (~30% of all MB neurons). This poses an intriguing question as to how those MB neurons distinguish punishment versus reward information delivered by dDA1 to generate avoidance versus preference behavioral output. The key to answering this question may be intracellular effectors in the MB neuropil. rut-AC is crucial in the MB247-GAL4-expressing MB neurons for both aversive and appetitive learning (Schwaerzel, 2003). Notably, rut mutants retain some learning capacities in electric shock- and sugar-mediated conditioning, whereas MB-less flies or the flies with inhibited MB synaptic output exhibit no trace of learning in both assays. This implicates additional cellular components crucial for aversive and appetitive memory formation. Because dumb mutants are rather completely impaired in aversive learning, dDA1 may activate rut-AC and other cellular components in the MB to process punishment information (Kim, 2007b).

G-protein-coupled receptors including dopamine receptors can recruit multiple effector systems through heteromeric G-proteins or through cross-interactions of diverse signaling components. Thus, for aversive learning, dDA1 activated by electric shock US input may recruit the mitogen-activated protein (MAP) kinase cascade in addition to the cAMP pathway. The activated protein kinase A and MAP kinases may act on ion channels or cell adhesion molecules such as integrin and FasII to modify MB synaptic output, leading to avoidance behavior. Consistently, the flies defective in 14-3-3 and S6KII, which are involved in the MAP kinase cascade, and α-integrin and fasII mutants are poor learners in electric shock-mediated conditioning (Kim, 2007b).

For reward-mediated learning, reward US input may impinge on at least two receptors, dDA1 and an octopamine receptor, in the MB. Their simultaneous activities may recruit multiple effectors that possibly include rut-AC, MAP kinases, protein kinase C, and CaM kinase II. The biochemical changes collectively activated by these effectors may alter MB synaptic output to generate preference behavior. Interestingly, OAMB (octopamine receptor) activates the increases in intracellular calcium as well as cAMP (Han, 1998) and is a good candidate that can turn on the aforementioned effectors for processing reward information in the MB. The punishment and reward effectors may be at work in separate areas of the same MB neuropil or in different MB neurons or neuropils, which are differentially innervated by dopaminergic axons conveying electric shock input or by dopaminergic and octopaminergic axons conveying sugar input. At present, there is limited information on intracellular components involved in appetitive learning. Future studies in this venue will help attest this model. Together, concurrent CS+ and US received during training may activate dDA1 (for punishment US) or dDA1 and an octopamine receptor (for reward US) to induce distinctive biochemical changes, leading to avoidance or preference behavior, respectively (Kim, 2007b).

Multiple lines of evidence indicate that dopamine in the amygdala, the nucleus accumbens, and the medial prefrontal cortex in mammals is crucial for acquisition, expression, and/or extinction in aversive pavlovian conditioning (for review, see Pezze, 2004). However, the receptors mediating the functions of dopamine are unclear. Studies using D1/D5 dopamine receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) in rats suggest the significant roles of the D1-type receptor in the amygdala and the nucleus accumbens during acquisition in fear conditioning and conditioned taste aversion (CTA), respectively (Guarraci, 1999; Fenu, 2001). However, the mice lacking D1 or D5 receptor show normal acquisition in fear conditioning (El-Ghundi, 2001; Holmes, 2001). Likewise, D1-deficient mice show normal learning of CTA to salt (CS) paired with LiCl (US), although they do not develop CTA to sucrose (Cannon, 2005). The discrepant findings of the pharmacological and genetic studies may be attributable to either other receptor types affected by SCH23390 or compensatory adaptations in D1 or D5 knock-out mice. The studies reported in this study support the latter and clarify the indispensable role of D1 receptor in aversive pavlovian conditioning. Additionally, pharmacological studies reveal the significant role of D1-type receptors in appetitive pavlovian conditioning in mammals (Schroeder, 2000; Baker, 2003; Eyny, 2003; Dalley, 2005) and possibly in Aplysia (Reyes, 2005), although no information is available on D1 or D5 knock-out mice in this type of behavioral plasticity. Therefore, the studies described here elucidate, for the first time, the critical role of D1 receptor in appetitive pavlovian conditioning (Kim, 2007b).

Octopamine and Dopamine differentially modulate the nicotine-induced calcium response in Drosophila Mushroom Body Kenyon Cells

In Drosophila associative olfactory learning, an odor, the conditioned stimulus (CS), is paired to an unconditioned stimulus (US). The CS and US information arrive at the Mushroom Bodies (MB), a Drosophila brain region that processes the information to generate new memories. It has been shown that olfactory information is conveyed through cholinergic inputs that activate nicotinic acetylcholine receptors (nAChRs) in the MB, while the US is coded by biogenic amine (BA) systems that innervate the MB. In this regard, the MB acts as a coincidence detector. A better understanding of the properties of the responses gated by nicotinic and BA receptors are required to get insights on the cellular and molecular mechanisms responsible for memory formation. In recent years, information has become available on the properties of the responses induced by nAChR activation in Kenyon Cells (KCs), the main neuronal MB population. However, very little information exists on the responses induced by aminergic systems in fly MB. This study evaluated some of the properties of the calcium responses gated by Dopamine (DA) and Octopamine (Oct) in identified KCs in culture. Exposure to BAs induces a fast but rather modest increase in intracellular calcium levels in cultured KCs. The responses to Oct and DA are fully blocked by a Voltage-gated Calcium Channel (VGCC) blocker, while they are differentially modulated by cAMP. Moreover, co-application of BAs and nicotine has different effects on intracellular calcium levels: while DA and nicotine effects are additive, Oct and nicotine induce a synergistic increase in calcium levels. These results suggest that a differential modulation of nicotine-induced calcium increase by DA and Oct could contribute to the events leading to learning and memory in flies (Leyton, 2013).

Two DA receptors that share homology to vertebrate DA type 1 receptors are expressed in Drosophila MB, DAMB (Dopamine 1-like receptor 2 or Dop1R2) and dDA1/DmDOP1/DopR. These receptors have been cloned and expressed in heterologous systems, where they are positively coupled to AC. Moreover, these receptors participate in the generation or modification of new olfactory memories in MB. The third cloned DA receptor, Dop2R/D2R, is not expressed in Drosophila MB. The current results are consistent with the general idea that DA receptors modulate intracellular cAMP levels, which could lead to the modification of the activity of VGCCs in KCs. The EC50 describe in this study is in agreement with previous studies in heterologous systems, which report EC50 in the range of 300-500 nM for both DA type 1 receptors. Thus, it is very likely that DAMB and/or dDA1/DmDOP1 are contributing to the DA-induced calcium response in Drosophila KCs. It would be expected that DA receptors increase cAMP levels to activate calcium currents in fly MB KCs. However, data using SQ22536 suggest that cAMP inhibits calcium fluxes in KCs. Although the cellular mechanisms responsible for this effect are not evident, it has been previously shown that increased cAMP signaling negatively modulates the activity of VGCCs through the activation of specific phosphatases in the vertebrate Nucleus Accumbens. Remarkably, the Nucleus Accumbens and MB are brain regions highly associated to the plastic behavioral effects induced by addictive drugs. Thus, it would not be particularly surprising to find similarities in the mechanisms responsible for the modulation of neuronal communication and excitability byDA in these two brain structures, as previously suggested.On the other hand, several Oct receptors have been previously cloned in Drosophila: one Oct receptor with high sequence homology to vertebrate -type receptors (Oct1R/OAMB) is expressed in dendrites and axons of the MB, and is the main candidate for the calcium responses induced by Oct in KCs, since the other cloned Oct receptors are not expressed in MB. In agreement with this, the calculated EC50, and the description that the response depends on VGCC activation and is independent on cAMP, further support this suggestion (Leyton, 2013).

An interaction of the neural systems responsible for CS and US stimuli in the MB region could mediate the generation of new memories. This interaction could occur at the presynaptic level, for instance, through the nAChR modulation of aminergic innervation to the MB region. However, the most accepted idea is that cholinergic and aminergic receptors expressed in MB KCs gate intracellular cascades that could cross-talk to modify the activity of KCs, a cellular event that could underlie long-lasting changes responsible for the generation of new olfactory memories in the fly (Leyton, 2013).

Although the modulation of nAChR-elicited responses by BAs in MB KCs is not a new idea in the field, direct evidence to support this proposition is limited. Previous studies have shown that DA modifies the acetylcholine-induced calcium response detected in MB in an in vivo fly brain preparation. That data show that this modulation depends on cAMP signaling. In addition to this, it has been shown that the enhancement in synaptic transmission between antennal lobe neurons and MB KCs in vitro depends on the activation of different receptors including dDA1/DmDOP1 and nAChRs. All these data support the idea that dopaminergic systems modulate the properties of the cholinergic responses in KCs. The proposition that Oct modulates nicotinic responses has not been previously evaluated. It is an interesting observation that the amines differentially modulate the calcium increase observed in presence of nicotine: while Oct and nicotine induce a synergistic effect on intracellular calcium levels compared to the responses detected for each ligand, the effects of DA and nicotine are rather additive. It is also interesting that this synergistic event is only observed when KCs are exposed to nicotine in presence of a saturating concentration of Oct, and is not observed at a lower Oct concentration (Leyton, 2013).


GENE STRUCTURE

cDNA clone length - 2538

Bases in 5' UTR - 365

Exons - 6

Bases in 3' UTR - 637

PROTEIN STRUCTURE

Amino Acids - 511

Structural Domains

Members of the superfamily of G-protein coupled receptors share significant similarities in sequence and transmembrane architecture. A Drosophila homologue of the mammalian dopamine receptor family has been isolated using a low stringency hybridization approach. The deduced amino acid sequence is approximately 70% homologous to the human D1/D5 receptors. When expressed in HEK 293 cells, the Drosophila receptor stimulates cAMP production in response to dopamine application. This effect was mimicked by SKF 38393, a specific D1 receptor agonist, but inhibited by dopaminergic antagonists such as butaclamol and flupentixol. In situ hybridization revealed that the Drosophila dopamine receptor is highly expressed in the somata of the optic lobes. This suggests that the receptor might be involved in the processing of visual information and/or visual learning in invertebrates (Gotzes, 1994).

Molecular cloning revealed the existence of at least five pharmacologically different dopamine receptors in vertebrates. Functionally, dopamine receptors either activate (D1-type), inhibit or do not interact with adenylate cyclase (D2-type). A recently cloned dopamine receptor from Drosophila melanogaster shares many structural and functional properties with vertebrate D1-type receptors but the pharmacological properties are very different. In contrast to most aminergic receptors, DmDop1 contains a long N-terminal extension. This study describes a deletion-mutagenesis approach to study whether the N-terminus of DmDop1 participates in receptor-ligand interactions. All mutants gave rise to functional receptors after heterologous expression in HEK 293 cells. The pharmacological properties, however, remained unchanged. A comparison of DNA and deduced amino acid sequences revealed that some Drosophila strains express a truncated version of the DmDop1 receptor (Gotzes, 1996).

A cDNA clone has been isolated from Drosophila displaying, within putative transmembrane domains, highest amino acid sequence homology (49%-53%) to members of the vertebrate dopamine D1-like receptor family. When expressed in either Sf9 or COS-7 cells, dDA1 did not bind the specific D1-like receptor antagonist [3H]SCH-23390 or numerous other dopaminergic, adrenergic or serotoninergic ligands with high affinity. However, like vertebrate dopamine D1-like receptors, dDA1 stimulated the accumulation of cAMP in response to DA. The dopaminergic rank order of potency (DA --> NE -->> 5-HT) and the lack of stimulation by other possible neurotransmitters (octopamine, tyramine, tryptamine) or DA metabolites (e.g. N-acetyl dopamine) found in Drosophila suggests that this receptor functionally belongs to the dopamine D1-like subfamily. Benzazepines, which characteristically bind to vertebrate dopamine D1-like receptors with high affinity, were relatively poor in stimulating dDA1-mediated accumulation of cAMP. Of the numerous compounds tested, a few dopaminergic antagonists inhibited DA-stimulated production of cAMP in a concentration-dependent manner, albeit with considerably reduced affinity. In situ hybridization revealed that dDA1 receptor mRNA is expressed as a maternal transcript, and at later blastoderm stages is restricted to apical regions of the cortical peripheral cytoplasm. The generation of inter-species D1 receptor chimeras may help to identify those particular sequence-specific motifs or amino acid residues conferring high affinity benzaepine receptor interactions (Sugamori, 1995; full text of article).


Dopamine receptor: Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

date revised: 15 April 2014

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