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J. Biol. Chem., Vol. 278, Issue 42, 41167-41172, October 17, 2003

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Merlin Links to the cAMP Neuronal Signaling Pathway by Anchoring the RI Subunit of Protein Kinase A^*

Mikaela Grönholm  , Lutz Vossebein ¶, Cathrine R. Carlson ||, Juha Kuja-Panula **, Tambet Teesalu , Kaija Alfthan , Antti Vaheri , Heikki Rauvala **, Friedrich W. Herberg ¶¶, Kjetil Taskén || and Olli Carpén 

From the Biomedicum Helsinki, Department of Pathology, ^**Neuroscience Center, Institute of Biotechnology, Departments of Biosciences and Virology, University of Helsinki and Helsinki University Central Hospital, 00014 Helsinki, Finland, the ^¶Ruhr-Universität Bochum, Institut für Physiologische Chemie, D-44780 Bochum, Germany, the ^||Department of Medical Biochemistry, University of Oslo, N-0317 Oslo, Norway, the Tartu Central Hospital, 50406 Tartu, Estonia, and the ^¶¶Universität Kassel, Institut für Biochemie, 34109 Kassel, Germany

The cAMP-protein kinase A (PKA) pathway, important in neuronal signaling, is regulated by molecules that bind and target PKA regulatory subunits. Of four regulatory subunits, RI is most abundantly expressed in brain. The RI knockout mouse has defects in hippocampal synaptic plasticity, suggesting a role for RI in learning and memory-related functions. Molecules that interact with or regulate RI are still unknown. We identified the neurofibromatosis 2 tumor suppressor protein merlin (schwannomin), a molecule related to the ezrin-radixin-moesin family of membrane-cytoskeleton linker proteins, as a binding partner for RI. Merlin and RI demonstrated a similar expression pattern in central nervous system neurons and an overlapping subcellular localization in cultured hippocampal neurons and transfected cells. The proteins were coprecipitated from brain lysates by cAMP-agarose and coimmunoprecipited from cellular lysates with specific antibodies. In vitro binding studies verified that the interaction is direct. The interaction appeared to be under conformational regulation and was mediated via the -helical region of merlin. Sequence comparison between merlin and known PKA anchoring proteins identified a conserved -helical PKA anchoring protein motif in merlin. These results identify merlin as the first neuronal binding partner for PKA-RI and suggest a novel function for merlin in connecting neuronal cytoskeleton to PKA signaling.

Received for publication, June 11, 2003 , and in revised form, July 28, 2003.

^* This work was supported by United States Army Neurofibromatosis Research Grant DAMD17-00-0550 and by grants from the Academy of Finland and the Norwegian Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Neuroscience Program, Biomedicum, PB 63, Haartmanink. 8, 00014 Helsinki, Finland. Tel.: 358-9-19125655; Fax: 358-9-47171964; E-mail: mikaela.gronholm{at}helsinki.fi.

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