Heteromerization of Ciliary G Protein-Coupled Receptors in the Mouse Brain

Green, Jill A.; Gu, Chen; Mykytyn, Kirk

doi:10.1371/journal.pone.0046304

Cited by 40 publications

(37 citation statements)

References 35 publications

(52 reference statements)

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“…To test whether Sstr3 localization to cilia is affected by agonist treatment, we generated primary cultures of wild-type (WT) mouse hippocampal neurons, which possess abundant Sstr3-positive cilia (40,41). The neurons were then treated with somatostatin (SST) for 0, 20, or 40 min, fixed, and colabeled with antibodies to Sstr3 and AC3, which is an established marker for neuronal cilia (26).…”

Section: Ciliary Localization Of Somatostatin Receptor Subtype 3 Is Dmentioning

confidence: 99%

Recruitment of β-Arrestin into Neuronal Cilia Modulates Somatostatin Receptor Subtype 3 Ciliary Localization

Green

Schmid

Bley

et al. 2016

Molecular and Cellular Biology

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c Primary cilia are essential sensory and signaling organelles present on nearly every mammalian cell type. Defects in primary cilia underlie a class of human diseases collectively termed ciliopathies. Primary cilia are restricted subcellular compartments, and specialized mechanisms coordinate the localization of proteins to cilia. Moreover, trafficking of proteins into and out of cilia is required for proper ciliary function, and this process is disrupted in ciliopathies. The somatostatin receptor subtype 3 (Sstr3) is selectively targeted to primary cilia on neurons in the mammalian brain and is implicated in learning and memory. Here, we show that Sstr3 localization to cilia is dynamic and decreases in response to somatostatin treatment. We further show that somatostatin treatment stimulates ␤-arrestin recruitment into Sstr3-positive cilia and this recruitment can be blocked by mutations in Sstr3 that impact agonist binding or phosphorylation. Importantly, somatostatin treatment fails to decrease Sstr3 ciliary localization in neurons lacking ␤-arrestin 2. Together, our results implicate ␤-arrestin in the modulation of Sstr3 ciliary localization and further suggest a role for ␤-arrestin in the mediation of Sstr3 ciliary signaling. P rimary cilia are typically solitary immotile cellular appendages that function as specialized sensory and signaling compartments (1-3). During mammalian development, primary cilia mediate critical developmental signaling pathways, including Hedgehog (Hh), Wnt, and transforming growth factor ␤ (TGF-␤) (4-6). Postnatally, primary cilia are nearly ubiquitous and are required to maintain cellular and tissue homeostasis. Primary ciliary dysfunction causes a class of human diseases, collectively referred to as ciliopathies, that present with a wide range of clinical features, including obesity, skeletal malformations, retinal degeneration, renal cystic disease, brain malformations, intellectual disability, and hypogonadism (7).Primary cilia are restricted compartments, and specialized mechanisms exist to coordinate the selective targeting, exclusion, and retention of certain proteins (8,9). This enrichment of select proteins is what defines the functions of cilia and determines the signaling pathways that they mediate. The importance of ciliary protein localization is highlighted by the fact that this process is disrupted in a subset of ciliopathies (10-12). Moreover, coordinated trafficking of proteins into and out of cilia is required for proper ciliary signaling. For example, in vertebrate Hh signaling, sonic Hedgehog binds to its receptor, Patched, on the ciliary membrane, causing it to exit the cilium. This allows the G protein-coupled receptor (GPCR)-like receptor Smoothened (Smo) to enter the cilium, which in turn impacts the activity of Gli transcription factors (13-16). In addition, ciliary signaling can be modulated by protein trafficking in the cilium. For example, in the photoreceptor outer segment, which is a modified primary cilium, light-induced activation of rhodopsin stim...

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Section: Ciliary Localization Of Somatostatin Receptor Subtype 3 Is Dmentioning

confidence: 99%

Recruitment of β-Arrestin into Neuronal Cilia Modulates Somatostatin Receptor Subtype 3 Ciliary Localization

Green

Schmid

Bley

et al. 2016

Molecular and Cellular Biology

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“…Neuronal cilia are also enriched for type 3 adenylyl cyclase (Bishop et al, 2007). It is noteworthy that different GPCRs can colocalize within the same neuronal cilium forming heteromers (Green et al, 2012). As discussed above and previously proposed by our group (Agnati et al, 1982(Agnati et al, , 1983(Agnati et al, , 2010bFuxe and Agnati, 1985;Guidolin et al, 2015), GPCR-GPCR receptor-receptor interactions can lead to changes in ligand binding properties, receptor desensitization, and internalization or can even lead to the activation of completely new intracellular decoding molecular pathways.…”

Section: Introductionmentioning

confidence: 62%

“…These phenomena can likely have peculiar importance for the complex functions of multifunctional sensory nano-antenna carried out by the primary cilia (Handel et al, 1999;Brailov et al, 2000;Green et al, 2012).…”

Section: The Multi Facet Aspects Of Cell Sentiencementioning

confidence: 99%

The multi-facet aspects of cell sentience and their relevance for the integrative brain actions: role of membrane protein energy landscape

Agnati¹,

Marcoli

Maura

et al. 2016

Reviews in the Neurosciences

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AbstractSeveral ion channels can be randomly and spontaneously in an open state, allowing the exchange of ion fluxes between extracellular and intracellular environments. We propose that the random changes in the state of ion channels could be also due to proteins exploring their energy landscapes. Indeed, proteins can modify their steric conformation under the effects of the physicochemical parameters of the environments with which they are in contact, namely, the extracellular, intramembrane and intracellular environments. In particular, it is proposed that the random walk of proteins in their energy landscape is towards attractors that can favor the open or close condition of the ion channels and/or intrinsic activity of G-protein-coupled receptors. The main aspect of the present proposal is that some relevant physicochemical parameters of the environments (e.g. molecular composition, temperature, electrical fields) with which some signaling-involved plasma membrane proteins are in contact alter their conformations. In turn, these changes can modify their information handling via a modulatory action on their random walk towards suitable attractors of their energy landscape. Thus, spontaneous and/or signal-triggered electrical activities of neurons occur that can have emergent properties capable of influencing the integrative actions of brain networks. Against this background, Cook’s hypothesis on ‘cell sentience’ is developed by proposing that physicochemical parameters of the environments with which the plasma-membrane proteins of complex cellular networks are in contact fulfill a fundamental role in their spontaneous and/or signal-triggered activity. Furthermore, it is proposed that a specialized organelle, the primary cilium, which is present in most cells (also neurons and astrocytes), could be of peculiar importance to pick up chemical signals such as ions and transmitters and to detect physical signals such as pressure waves, thermal gradients, and local field potentials.

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“…Nucleic acids were stained with DRAQ5 (Axxora). Immunofluorescence procedures have been described (54). Samples were imaged either on a Zeiss LSM 510 laser scanning confocal microscope at the Hunt-Curtis Imaging Facility in the Department of Neuroscience at OSU or an Andor Revolution WD spinning disk confocal imaging system at the Ohio State University Neuroscience Center Imaging Core.…”

Section: Methodsmentioning

confidence: 99%

Primary cilia enhance kisspeptin receptor signaling on gonadotropin-releasing hormone neurons

Koemeter-Cox

Sherwood

Green

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Most central neurons in the mammalian brain possess an appendage called a primary cilium that projects from the soma into the extracellular space. The importance of these organelles is highlighted by the fact that primary cilia dysfunction is associated with numerous neuropathologies, including hyperphagia-induced obesity, hypogonadism, and learning and memory deficits. Neuronal cilia are enriched for signaling molecules, including certain G protein-coupled receptors (GPCRs), suggesting that neuronal cilia sense and respond to neuromodulators in the extracellular space. However, the impact of cilia on signaling to central neurons has never been demonstrated. Here, we show that the kisspeptin receptor (Kiss1r), a GPCR that is activated by kisspeptin to regulate the onset of puberty and adult reproductive function, is enriched in cilia projecting from mouse gonadotropin-releasing hormone (GnRH) neurons. Interestingly, GnRH neurons in adult animals are multiciliated and the percentage of GnRH neurons possessing multiple Kiss1r-positive cilia increases during postnatal development in a progression that correlates with sexual maturation. Remarkably, disruption of cilia selectively on GnRH neurons leads to a significant reduction in kisspeptin-mediated GnRH neuronal activity. To our knowledge, this result is the first demonstration of cilia disruption affecting central neuronal activity and highlights the importance of cilia for proper GPCR signaling.GPR54 | neuronal primary cilia | electrophysiology

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Heteromerization of Ciliary G Protein-Coupled Receptors in the Mouse Brain

Cited by 40 publications

References 35 publications

Recruitment of β-Arrestin into Neuronal Cilia Modulates Somatostatin Receptor Subtype 3 Ciliary Localization

Recruitment of β-Arrestin into Neuronal Cilia Modulates Somatostatin Receptor Subtype 3 Ciliary Localization

The multi-facet aspects of cell sentience and their relevance for the integrative brain actions: role of membrane protein energy landscape

Primary cilia enhance kisspeptin receptor signaling on gonadotropin-releasing hormone neurons

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