PubMed Journals: J Biol Chem

  Source:		PMID: 9468536

    		J Biol Chem. 1998 Feb 20;273(8):4734-9.
			Transgenic approaches to define the functional
			role of dual site phospholamban phosphorylation.

			Luo W(1), Chu G, Sato Y, Zhou Z, Kadambi
			VJ, Kranias EG.

			Author Information
			(1) Department of Pharmacology and Cell
			Biophysics, University of Cincinnati College
			of Medicine, Cincinnati, Ohio 45267-0575,

			Phospholamban is a critical regulator of
			the sarcoplasmic reticulum Ca2+-ATPase activity
			and myocardial contractility. Phosphorylation
			of phospholamban occurs on both Ser16 and
			Thr17 during isoproterenol stimulation.
			To determine the physiological significance of dual
			site phospholamban phosphorylation, we generated
			transgenic models expressing either wild-type
			or the Ser16 --> Ala mutant phospholamban
			in the cardiac compartment of the phospholamban
			knockout mice. Transgenic lines with similar
			levels of mutant or wild-type phospholamban
			were studied in parallel. Langendorff perfusion
			indicated that the basal hyperdynamic cardiac
			function of the knockout mouse was reversed
			to the same extent by reinsertion of either
			wild-type or mutant phospholamban. However,
			isoproterenol stimulation was associated
			with much lower responses in the contractile
			parameters of mutant phospholamban compared
			with wild-type hearts. These attenuated
			responses were due to lack of phosphorylation
			of mutant phospholamban, assessed in 32P
			labeling perfusion experiments. The lack
			of phospholamban phosphorylation in vivo
			was not due to conversion of Ser16 to Ala,
			since the mutated phospholamban form could
			serve as substrate for the
			calcium-calmodulin-dependent protein kinase
			in vitro. These findings indicate that
			phosphorylation of Ser16 is a prerequisite
			for Thr17 phosphorylation in phospholamban,
			and prevention of phosphoserine formation
			results in attenuation of the beta-agonist
			stimulatory responses in the mammalian heart.

			PMID: 9468536 [Indexed for MEDLINE]

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