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© The Rockefeller University Press, 0021-9525/2000/1/147/ $5.00
The Journal of Cell Biology, Volume 148, Number 1, January 10, 2000 147-158

Original Article

PSD-95 and SAP97 Exhibit Distinct Mechanisms for Regulating K+ Channel Surface Expression and Clustering

Amanda M. Tiffanya,b, Louis N. Manganasa,b,c, Eunjoon Kimc, Yi-Ping Hsuehc, Morgan Shengc, and James S. Trimmera,b,c
a Department of Biochemistry and Cell Biology, State University of New York, Stony Brook, New York 11794-5215
b Institute for Cell and Developmental Biology, State University of New York, Stony Brook, New York 11794-5215
c Howard Hughes Medical Institute, Massachusetts General Hospital, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02214

Correspondence to: James S. Trimmer, Department of Biochemistry and Cell Biology, SUNY at Stony Brook, Stony Brook, NY 11794-5215. Tel:(516) 632-9171 Fax:(516) 632-9714 E-mail:james.trimmer{at}sunysb.edu.

Mechanisms of ion channel clustering by cytoplasmic membrane-associated guanylate kinases such as postsynaptic density 95 (PSD-95) and synapse-associated protein 97 (SAP97) are poorly understood. Here, we investigated the interaction of PSD-95 and SAP97 with voltage-gated or Kv K+ channels. Using Kv channels with different surface expression properties, we found that clustering by PSD-95 depended on channel cell surface expression. Moreover, PSD-95–induced clusters of Kv1 K+ channels were present on the cell surface. This was most dramatically demonstrated for Kv1.2 K+ channels, where surface expression and clustering by PSD-95 were coincidentally promoted by coexpression with cytoplasmic Kvß subunits. Consistent with a mechanism of plasma membrane channel–PSD-95 binding, coexpression with PSD-95 did not affect the intrinsic surface expression characteristics of the different Kv channels. In contrast, the interaction of Kv1 channels with SAP97 was independent of Kv1 surface expression, occurred intracellularly, and prevented further biosynthetic trafficking of Kv1 channels. As such, SAP97 binding caused an intracellular accumulation of each Kv1 channel tested, through the accretion of SAP97 channel clusters in large (3–5 µm) ER-derived intracellular membrane vesicles. Together, these data show that ion channel clustering by PSD-95 and SAP97 occurs by distinct mechanisms, and suggests that these channel-clustering proteins may play diverse roles in regulating the abundance and distribution of channels at synapses and other neuronal membrane specializations.

Key Words: ion channel localization, protein binding, COS cells, membrane proteins, nerve tissue proteins


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