Dopamine Receptor Type 5 in the Primary Cilia Has Dual Chemo- and Mechano-Sensory Roles

Abdul-Majeed, Shakila; Nauli, Surya M.

doi:10.1161/hypertensionaha.111.172080

Cited by 78 publications

(85 citation statements)

References 37 publications

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“…In contrast, knockdown of CaV1.2 significantly shortened cilia length in Pkd groups. This observation is intriguing because shorter cilia were often related to less sensitivity to extracellular cues, such as fluid-flow shear stress [26,27]. Also noteworthy is that Pkd1 −/− and Pkd2 −/− cell lines had longer cilia compared to wild-type cells.…”

Section: Resultsmentioning

confidence: 99%

L-type calcium channel modulates cystic kidney phenotype

Jin

Muntean

Aal-Aaboda

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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In polycystic kidney disease (PKD), abnormal proliferation and genomic instability of renal epithelia have been associated with cyst formation and kidney enlargement. We recently showed that L-type calcium channel (Cav1.2) is localized to primary cilia of epithelial cells. Previous studies have also shown that low intracellular calcium level was associated with the hyperproliferation phenotype in the epithelial cells. However, the relationship between calcium channel and cystic kidney phenotype is largely unknown. In this study, we generated cells with somatic deficient Pkd1 or Pkd2 to examine ciliary CaV1.2 function via lentiviral knockdown or pharmacological verapamil inhibition. Although inhibition of CaV1.2 expression or function did not change division and growth patterns in wild-type epithelium, it led to hyperproliferation and polyploidy in mutant cells. Lack of CaV1.2 in Pkd mutant cells also decreased the intracellular calcium level. This contributed to a decrease in CaM kinase activity, which played a significant role in regulating Akt and Erk signaling pathways. Consistent with our in vitro results, CaV1.2 knockdown in zebrafish and Pkd1 heterozygous mice facilitated the formation of kidney cysts. Larger cysts were developed faster in Pkd1 heterozygous mice with CaV1.2 knockdown. Overall, our findings emphasized the importance of CaV1.2 expression in kidneys with somatic Pkd mutation. We further suggest that CaV1.2 could serve as a modifier gene to cystic kidney phenotype.

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Section: Resultsmentioning

confidence: 99%

L-type calcium channel modulates cystic kidney phenotype

Jin

Muntean

Aal-Aaboda

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Although both structure and function of primary cilium are required for its sensory functions, analysis of cilium functionevenin cells with a known structural defect isrecommended, as cilium length and function may not be well correlated (Abdul-Majeed et al, 2012; Abdul-Majeed & Nauli, 2011b). Calcium is the most universal second messenger, which has been associated with mechanisms involved in cilia-related cystic phenotypes (Abdul-Majeed & Nauli, 2011a; Nauli & Zhou, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…The best way to identify the optimal length of cilia is by studying the association between the cilium length and function (Nauli et al, 2008). In general, the longer the cilia, the more sensitive they are to being bent and activated by fluid-shear stress (Abdul-Majeed, Moloney, & Nauli, 2012; Abdul-Majeed & Nauli, 2011b). However, long cilia are less stable and can fall off easily, resulting in cells without cilia.…”

Section: Identification Of Primary Ciliummentioning

confidence: 99%

Non-Motile Primary Cilia as Fluid Shear Stress Mechanosensors

Nauli¹,

Jin²,

AbouAlaiwi³

et al. 2013

Methods in Enzymology

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Primary cilia are sensory organelles that transmit extracellular signals into intracellular biochemical responses. Structural and functional defects in primary cilia are associated with a group of human diseases, known as ciliopathies, with phenotypes ranging from cystic kidney and obesity to blindness and mental retardation. Primary cilia mediate mechano- and chemosensation in many cell types. The mechanosensory function of the primary cilia requires the atypical G-protein-coupled receptor polycystin-1 and the calcium-permeable nonselective cation channel polycystin-2. Mechanical stimulations such as fluid-shear stress of the primary cilia initiate intracellular calcium rise, nitric oxide release, and protein modifications. In this review, we describe a set of protocols for cell culture to promote ciliation, mechanical stimulations of the primary cilia, and measurements of calcium rise and nitric oxide release induced by fluid shear stress.

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“…Although G s -coupled ␤ 2 -adrenoceptors did not respond to mechanical stimuli (62,115), there is growing evidence that other G s -coupled receptors might be inherently mechanosensitive. Recently, dopamine D 5 receptors in primary cilia were described as mechanosensors (1). Furthermore, in bone cells the parathyroid hormone type-1 receptor coupling to both G s and G q/11 proteins was shown to be activated by fluid shear stress (114).…”

Section: Gpcrs As Mechanosensorsmentioning

confidence: 99%

G protein-mediated stretch reception

Storch¹,

Schnitzler

Gudermann

2012

American Journal of Physiology-Heart and Circulatory Physiology

155

136

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Mechanosensation and -transduction are important for physiological processes like the senses of touch, hearing, and balance. The mechanisms underlying the translation of mechanical stimuli into biochemical information by activating various signaling pathways play a fundamental role in physiology and pathophysiology but are only poorly understood. Recently, G protein-coupled receptors (GPCRs), which are essential for the conversion of light, olfactory and gustatory stimuli, as well as of primary messengers like hormones and neurotransmitters into cellular signals and which play distinct roles in inflammation, cell growth, and differentiation, have emerged as potential mechanosensors. The first candidate for a mechanosensitive GPCR was the angiotensin-II type-1 (AT 1) receptor. Agonist-independent mechanical receptor activation of AT 1 receptors induces an active receptor conformation that appears to differ from agonist-induced receptor conformations and entails the activation of G proteins. Mechanically induced AT 1 receptor activation plays an important role for myogenic vasoconstriction and for the initiation of cardiac hypertrophy. A growing body of evidence suggests that other GPCRs are involved in mechanosensation as well. These findings highlight physiologically relevant, ligand-independent functions of GPCRs and add yet another facet to the polymodal activation spectrum of this ubiquitous protein family. mechanosensation; G protein-coupled receptor; angiotensin-II type-1 receptor; agonist independent THIS ARTICLE is part of a collection on G Protein Kinase A Signaling in Cardiovascular Physiology and Disease. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology. org/.

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Dopamine Receptor Type 5 in the Primary Cilia Has Dual Chemo- and Mechano-Sensory Roles

Cited by 78 publications

References 37 publications

L-type calcium channel modulates cystic kidney phenotype

L-type calcium channel modulates cystic kidney phenotype

Non-Motile Primary Cilia as Fluid Shear Stress Mechanosensors

G protein-mediated stretch reception

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