RT Journal Article SR Electronic T1 The α-Syntrophin PH and PDZ Domains Scaffold Acetylcholine Receptors, Utrophin, and Neuronal Nitric Oxide Synthase at the Neuromuscular Junction JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 11004 OP 11010 DO 10.1523/JNEUROSCI.1930-10.2010 VO 30 IS 33 A1 Adams, Marvin E. A1 Anderson, Kendra N. E. A1 Froehner, Stanley C. YR 2010 UL http://www.jneurosci.org/content/30/33/11004.abstract AB At the neuromuscular junction (NMJ), the dystrophin protein complex provides a scaffold that functions to stabilize acetylcholine receptor (AChR) clusters. Syntrophin, a key component of that scaffold, is a multidomain adapter protein that links a variety of signaling proteins and ion channels to the dystrophin protein complex. Without syntrophin, utrophin and neuronal nitric oxide synthase μ (nNOSμ) fail to localize to the NMJ and the AChRs are distributed abnormally. Here we investigate the contribution of syntrophin domains to AChR distribution and to localization of utrophin and nNOSμ at the NMJ. Transgenic mice expressing α-syntrophin lacking portions of the first pleckstrin homology (PH) domain (ΔPH1a or ΔPH1b) or the entire PDZ domain (ΔPDZ) were bred onto the α-syntrophin null background. As expected the ΔPDZ transgene did not restore the NMJ localization of nNOS. The ΔPH1a transgene did restore postsynaptic nNOS but surprisingly did not restore sarcolemmal nNOS (although sarcolemmal aquaporin-4 was restored). Mice lacking the α-syntrophin PDZ domain or either half of the PH1 domain were able to restore utrophin to the NMJ but did not correct the aberrant AChR distribution of the α-syntrophin knock-out mice. However, mice expressing both the transgenic ΔPDZ and the transgenic ΔPH1a constructs did restore normal AChR distribution, demonstrating that both domains are required but need not be confined within the same protein to function. We conclude that the PH1 and PDZ domains of α-syntrophin work in concert to facilitate the localization of AChRs and nNOS at the NMJ.