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First published on May 17, 2007; DOI: 10.1124/mol.107.037747

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Received for publication May 3, 2007.
Revised May 16, 2007.
Accepted for publication May 16, 2007.

NSF Regulates {beta}2 Adrenoceptors Trafficking and Signaling in Cardiomyocytes

Yongyu Wang 1, Benjamin Lauffer 2, Mark Von Zastrow 2, Brian Kobilka 3, Yang Xiang 1*

1 University of Illinois at Urbana Champaign 2 University of California at San Francisco 3 Stanford University

* Address correspondence to: E-mail: kevinyx{at}life.uiuc.edu

Abstract

Recycling of G protein-coupled receptors (GPCRs) determines the functional resensitization of receptors and is implicated in switching {beta}2 adrenoceptor ({beta}2AR) G protein specificity in cardiomyocytes. The human {beta}2AR carboxyl end binds to the N-ethylmaleimide-sensitive factor (NSF), an ATPase integral to membrane trafficking machinery. Interestingly, the human {beta}2AR (h{beta}2AR) carboxyl end pulled down NSF from mouse heart lysates whereas the murine one did not. Despite this difference, both {beta}2ARs exhibited substantial agonist-induced internalization, recycling, and Gi coupling in cardiomyocytes. The h{beta}2AR, however, displayed faster rates of agonist-induced internalization and recycling when compared to the m{beta}2AR; and a more profound Gi component in its contraction response. Replacing the m{beta}2AR proline (-1) with a leucine generated a gain-of-function mutation, m{beta}2AR-P417L, with a rescued ability to bind NSF, faster internalization and recycling than the m{beta}2AR, and a significant enhancement in Gi signaling, which mimics the h{beta}2AR. Selective disruption of the m{beta}2AR-P417L binding to NSF inhibited the receptor coupling to Gi. Meanwhile, inhibiting NSF with N-ethylmaleimide blocked the m{beta}2AR recycling following agonist-induced endocytosis. Expressing the NSF E329Q mutant lacking ATPase activity inhibited the m{beta}2AR coupling to Gi in cardiomyocytes. Our results revealed a dual regulation on h{beta}2AR trafficking and signaling by NSF through direct binding to cargo receptor and its ATPase activity, and uncovered an unprecedented role for the receptor binding to NSF in regulating G protein specificity that has diverged between mouse and human {beta}2ARs.


Key words: Adrenergic, Gi family, Gs family, G protein regulation, Desensitization/uncoupling, Sequestration/Internalization, Recycling


This article has been cited by other articles:


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Y. Wang, V. De Arcangelis, X. Gao, B. Ramani, Y.-s. Jung, and Y. Xiang
Norepinephrine- and Epinephrine-induced Distinct 2-Adrenoceptor Signaling Is Dictated by GRK2 Phosphorylation in Cardiomyocytes
J. Biol. Chem., January 25, 2008; 283(4): 1799 - 1807.
[Abstract] [Full Text] [PDF]


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