Reference Report

Reference
Citation	Gao, Z., Joseph, E., Ruden, D.M., Lu, X. (2004). Drosophila Pkd2 is haploid-insufficient for mediating optimal smooth muscle contractility. J. Biol. Chem. 279(14): 14225--14231. (Export to RIS)
FlyBase ID	FBrf0174776
Publication Type	Research paper
PubMed ID	14732716
PubMed Abstract	Humans heterozygous for PKD1 or PKD2 develop autosomal dominant polycystic kidney disease, a common genetic disorder characterized by renal cyst formation and extrarenal complications such as hypertension and vascular aneurysms. Cyst formation requires the somatic inactivation of the wild type allele. However, it is unknown whether this recessive mechanism applies to life-threatening vascular aneurysms, which could involve weakening of the endothelial lining or surrounding vascular smooth muscle cells (SMCs). Drosophila Pkd2 at 33E3 (Pkd2) encodes a PKD2 family of Ca(2+)-activated Ca(2+)-permeable cation channels. We show here that loss-of-function Pkd2 mutations severely reduced the contractility of the visceral SMCs, which was restored by expressing wild type Pkd2 cDNA via a muscle-specific Gal4 driver. The effect of Pkd2 mutations alone on the skeletal muscle was minimal but was exacerbated by ryanodine-induced perturbation of intracellular Ca(2+) stores. Consistent with this, Pkd2 interacted strongly with a ryanodine receptor mutation, causing a synergistic reduction of larval body wall contraction rate that is normally regulated through Ca(2+) oscillation during excitation-contraction coupling in the skeletal muscle. These results suggest that PKD2 cooperates with the ryanodine receptor to promote optimal muscle contractility through intracellular Ca(2+) homeostasis. Further genetic analysis indicated that Pkd2 is strongly haploinsufficient for normal SMC contractility. Since Ca(2+) homeostasis is a conserved mechanism for optimal muscle performance, our results raise the possibility that inactivation of just one PKD2 copy is sufficient to compromise vascular SMC contractility and function in PKD2 heterozygous patients, thus explaining their increased susceptibility to hypertension and vascular aneurysms.
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Language of Publication	English
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Publication Type	Journal
Abbreviation	J. Biol. Chem.
Title	Journal of Biological Chemistry
Publication Year	1905-
ISBN/ISSN	0021-9258
Data from Reference
Aberrations (4)
	Df(2L)esc-P3-0 Df(2L)prd1.7 Df(2L)Prl Dp(2;2)Pkd2^ko67
Alleles (8)
	Avic\GFP^Scer\UAS.cUa Pkd2^ko67.3' Pkd2^ko67.5' Pkd2^Scer\UAS.cGa Rya-r44F¹⁶ Rya-r44F^k04913 Scer\GAL4^how-24B Scer\GAL4^Pkd2.PG
Constructs (3)
	P{Pkd2-GAL4.G} P{UAS-GFP.U} P{UAS-Pkd2.F3112}
Genes (4)
	Avic\GFP Pkd2 Rya-r44F Scer\GAL4
Insertions (1)
	P{GawB}how^24B