Differential dopamine receptor subtype regulation of adenylyl cyclases in lipid rafts in human embryonic kidney and renal proximal tubule cells

Yu, Pingfeng; Sun, Min; Villar, Van Anthony M.; Zhang, Yanrong; Weinman, Edward J.; Felder, Robin A.; José, Pedro A.

doi:10.1016/j.cellsig.2014.07.003

Cited by 25 publications

(24 citation statements)

References 45 publications

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“…Alternatively, fenoldopam may increase production of adenylyl cyclases, augmenting forskolin stimulated cAMP production. This second notion is consistent with previous work indicating that fenoldopam treatment upregulates AC6, a specific adenylyl cyclase isoform, production in kidney cells (Yu et al, 2014). Our results support this possible molecular pathway by demonstrating an increase in AC6 mRNA expression in response to fenoldopam stimulation.…”

Section: Discussionsupporting

confidence: 93%

Lengthening primary cilia enhances cellular mechanosensitivity

Spasic¹,

Jacobs

2017

eCM

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The primary cilium is a mechanosensor in a variety of mammalian cell types, initiating and directing intracellular signaling cascades in response to external stimuli. When primary cilia formation is disrupted, cells have diminished mechanosensitivity and an abrogated response to mechanical stimulation. Due to this important role, we hypothesized that increasing primary cilia length would enhance the downstream response, and therefore, mechanosensitivity. To test this hypothesis, we increased osteocyte primary cilia length with fenoldopam and lithium and found that cells with longer primary cilia are more mechanosensitive. Furthermore, fenoldopam treatment potentiated adenylyl cyclase activity and was able to recover primary cilia form and sensitivity in cells with impaired cilia. This work demonstrates that modulating the structure of the primary cilium directly impacts cellular mechanosensitivity. Our results implicate cilium length as a potential therapeutic target for combating numerous conditions characterized by impaired cilia function.

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Section: Discussionsupporting

confidence: 93%

Lengthening primary cilia enhances cellular mechanosensitivity

Spasic¹,

Jacobs

2017

eCM

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“…Other cell adhesion molecules expressed by dopaminergic neurons include several that are likely to be concentrated in lipid raft zones via glycophosphatidyl inositol (GPI) anchors [39]. These lipid raft zones are enriched in dopamine, adenosine and other G-protein coupled receptors [53, 54]. The geometries of homomeric and heteromeric cell adhesion molecule recognition of their ligands on other neurons allow anchoring of such rafts in areas in which pre- and post-synaptic neurons are closely opposed to each other [39].…”

Section: Dopaminergic Systems and Cell Adhesion Molecules: How Thementioning

confidence: 99%

Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): plastic changes and neuroadaptations that may contribute to augmentation

Earley¹,

Uhl

Clemens

et al. 2017

Sleep Medicine

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Restless Legs Syndrome (RLS) is primarily treated with levodopa and dopaminergics that target the inhibitory dopamine receptor subtypes D3 and D2. The initial success of this therapy led to the idea of a hypo-dopaminergic state as the mechanistic origin underlying RLS. However, multiple lines of evidence suggest that this simplified concept of a reduced dopamine function as the basis of RLS is incomplete. Moreover, long-term medication with the D2/D3 agonists leads to a reversal of the initial benefits of dopamine agonists and augmentation, which is a worsening of symptoms under therapy. The recent findings on the state of the dopamine system in RLS that support the notion that a dysfunction in the dopamine system may in fact give rise to a hyper-dopaminergic state is summaraized. Based on this data, the concept of a dynamic nature of the dopamine effects in a circadian context, is presented. The possible interactions of cell-adhesion molecules expressed by dopaminergic systems and their possible impact on RLS and augmentation are discussed. Genome-wide association studies (GWAS) indicate a significantly increased risk for RLS in populations with genomic variants of the cell adhesion molecule receptor type protein tyrosine phosphatase D (PTPRD), and PTPRD is abundantly expressed by dopamine neurons. PTPRD may play a role in the reconfiguration of neural circuits, including shaping the interplay of G protein-coupled receptor (GPCR) homomers and heteromers that mediate dopaminergic modulation. Recent animal model data support the concept that interactions between functionally-distinct dopamine receptor subtypes can re-shape behavioral outcomes and change with normal aging. Additionally, long-term activation of one dopamine receptor subtype can increase receptor expression of a different receptor subtype with opposing modulatory actions. Such dopamine receptor interactions at both spinal and supra-spinal levels appear to play important roles in RLS. In addition, these interactions can also extend to the adenosine A2A receptor, which is also prominently expressed in the striatum. Interactions between A2A and dopamine receptors and dopaminergic cell adhesion molecules, including PTPRD, may provide new pharmacological targets in treating RLS. In summary, new treatment options for RLS that include recovery from augmentation will have to take into account dynamic changes to the dopamine system that occur during the circadian cycle, plastic changes that can develop as a function of treatment or with aging, changes to the connectome based on alterations to cell adhesion molecules, and receptor interactions that may reach beyond the dopamine system itself.

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“…Dopamine D1 receptors preferentially regulate AC3, AC5, and AC6 activity and this depends on interaction with lipid rafts, whereas dopamine D5 receptors are more nonraft localized and couple to just AC5 (Yu et al, 2014). Family B GPCRs also seem to depend upon colocalization of receptor and AC, as evidenced by the observation that the pituitary ACactivating polypeptide type 1 receptor was unable to signal to downstream effectors when AC6 (but not AC7) expression was knocked down (Emery et al, 2015).…”

Section: Compartmentation Of Adenylyl Cyclasesmentioning

confidence: 99%

“…ACs can be overexpressed in mammalian cells, HEK293 cells being a very popular model system . One should keep in mind that HEK293 cells endogenously express several mACs, providing background activity (Atwood et al, 2011;Yu et al, 2014). ACs can also be effectively overexpressed in Spodoptera frugiperda Sf9 cells (Taussig et al, 1994b).…”

Section: From Organs To Purified Adenylyl Cyclasesmentioning

confidence: 99%