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

Koemeter-Cox, Andrew Ian; Sherwood, Thomas W.; Green, Jill A.; Steiner, Robert A.; Berbari, Nicolas F.; Yoder, Bradley K.; Kauffman, Alexander S.; Monsma, Paula C.; Brown, Anthony; Askwith, Candice C.; Mykytyn, Kirk

doi:10.1073/pnas.1403286111

Cited by 81 publications

(74 citation statements)

References 57 publications

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“…However, the implications that 5-HT 6 receptors localize to primary neuronal cilia has received scant attention. Primary cilia are enriched with signaling proteins such as receptors and second messenger systems that allow them to function as neuronal sensory organelles that sample the extrasynaptic space (Koemeter-Cox et al , 2014; Louvi and Grove, 2011; Whitfield, 2004). This could be an important mechanism for integrating extracellular signals over a different time scale than that associated with synaptic neurotransmission.…”

Section: Discussionmentioning

confidence: 99%

5-HT 6 receptor blockade regulates primary cilia morphology in striatal neurons

et al. 2017

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The 5-HT6 receptor has been implicated in a variety of cognitive processes including habitual behaviors, learning, and memory. It is found almost exclusively in the brain, is expressed abundantly in striatum, and localizes to neuronal primary cilia. Primary cilia are antenna-like, sensory organelles found on most neurons that receive both chemical and mechanical signals from other cells and the surrounding environment; however, the effect of 5-HT6 receptor function on cellular morphology has not been examined. We confirmed that 5-HT6 receptors were localized to primary cilia in wild-type (WT) but not 5-HT6 knockout (5-HT6KO) in both native mouse brain tissue and primary cultured striatal neurons then used primary neurons cultured from WT or 5-HT6KO mice to study the function of these receptors. Selective 5-HT6 antagonists reduced cilia length in neurons cultured from wild-type mice in a concentration and time-dependent manner without altering dendrites, but had no effect on cilia length in 5-HT6KO cultured neurons. Varying the expression levels of heterologously expressed 5-HT6 receptors affected the fidelity of ciliary localization in both WT and 5-HT6KO neurons; overexpression lead to increasing amounts of 5-HT6 localization outside of the cilia but did not alter cilia morphology. Introducing discrete mutations into the third cytoplasmic loop of the 5-HT6 receptor greatly reduced, but did not entirely eliminate, trafficking of the 5-HT6 receptor to primary cilia. These data suggest that blocking 5-HT6 receptor activity reduces the length of primary cilia and that mechanisms that regulate trafficking of 5-HT6 receptors to cilia are more complex than previously thought.

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Section: Discussionmentioning

confidence: 99%

5-HT 6 receptor blockade regulates primary cilia morphology in striatal neurons

et al. 2017

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“…hormone receptor 1 (Mchr1) (10,21), dopamine receptor 1 (D1) (22), vasoactive intestinal receptor 2 (23), neuropeptide Y receptors 2 and 5 (24), and kisspeptin receptor 1 (25). These cilia are also widely enriched for the GPCR signaling element type 3 adenylyl cyclase (AC3) (26).…”

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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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“…Many BBS gene products form a large protein complex termed the BBSome (Nachury et al 2007). The BBSome functions in the localization of select transmembrane proteins to, and removal from, the cilium (Berbari et al 2008; Jin et al 2010; Domire et al 2011; Koemeter-Cox et al 2014; Liew et al 2014; Mourao et al 2014). …”

Section: Introductionmentioning

confidence: 99%

“…Some of these ciliary GPCRs include somatostatin receptor 3 (Sstr3), serotonin receptor 6 (5HT6), dopamine receptor 1 (Drd1), neuropeptide Y receptor 2 (Npy2r), and kisspeptin receptor 1 (Kiss1r) (Hamon et al 1999; Handel et al 1999; Brailov et al 2000; Schulz et al 2000; Marley and von Zastrow 2010; Domire et al 2011; Loktev and Jackson 2013; Koemeter-Cox et al 2014). While the functional significance of the localization of these receptors to cilia remains unclear, it is possible that they affect appetite, satiety, or metabolism, especially when given that somatostatin, serotonin, dopamine, neuropeptide Y, and kisspeptin, have all been implicated in either reward, feeding behaviors, metabolism, or glucose handling (Vijayan and McCann 1977; Pollock and Rowland 1981; Aponte et al 1984; Salamone et al 1990; Tolson et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Cilia and Obesity

Vaisse

Reiter

Berbari

2017

Cold Spring Harb Perspect Biol

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The ciliopathies Bardet – Biedl syndrome and Alström syndrome cause obesity. How ciliary dysfunction leads to obesity has remained mysterious, partly because of a lack of understanding of the physiological roles of primary cilia in the organs and pathways involved in the regulation of metabolism and energy homeostasis. Historically, the study of rare monogenetic disorders that present with obesity has informed our molecular understanding of the mechanisms involved in nonsyndromic forms of obesity. Here, we present a framework, based on genetic studies in mice and humans, of the molecular and cellular pathways underlying long-term regulation of energy homeostasis. We focus on recent progress linking these pathways to the function of the primary cilia with a particular emphasis on the roles of neuronal primary cilia in the regulation of satiety.

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

Cited by 81 publications

References 57 publications

5-HT 6 receptor blockade regulates primary cilia morphology in striatal neurons

5-HT 6 receptor blockade regulates primary cilia morphology in striatal neurons

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

Cilia and Obesity

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