Amphiphysin

Amphiphysin Nerve-terminal protein that associates with synaptic vesicles probably via AP2 bound to synaptotagmin. May function in endocytosis. 

Razzaq A, Robinson IM, McMahon HT, Skepper JN, Su Y, Zelhof AC, Jackson AP, Gay NJ, O Kane CJ (2001) Amphiphysin is necessary for organization of the excitation-contraction coupling machinery of muscles, but not for synaptic vesicle endocytosis in Drosophila. Genes Dev. 15 2967-2979. 

For the formation of clathrin-coated vesicles, several proteins are required. Currently, there are several recombinant inhibitors available, which block different steps of coated pit/vesicle formation for example, amphiphysin (53), clathrin assembly protein AP180 (54), epsin (55), and clathrin mutant (56). 

Wigge P, Vallis Y, McMahon HT. Inhibition of receptor-mediated enocytosis by the amphiphysin SH3 domain. Curr Biol 1997 7(8) 554-560. 

In the kiss-and-run mode exocytosis and endocytosis are directly coupled to each other, while in the case of classical complete vesicle fusion, exocytosis and slow clathrin-mediated endocytosis are timely and spatially separated. However, it appears that also in the latter case exocytosis and endocytosis occur coordinated, as both are stimulated by an increase of the cytoplasmic calcium concentration. It has been shown that after calcium entry the enzyme phospho-inositol-5 kinase Iy, which is enriched in the synapse, catalyzes the synthesis of phosphatidylinos-itol (4,5)-bisphosphate and that this mechanism is important for synaptic vesicle trafficking (Di Paolo et al. 2004). As many proteins involved in clathrin-mediated endocytosis are recruited to the plasma membrane by binding to phosphatidylinosi-tol (4,5)-bisphosphate (e.g., amphiphysin, dynamin, epsin, AP-180, and AP-2) it is attractive to speculate that elevated levels of calcium mediate the recruitment of en-docytic proteins to the plasma membrane by this mechanism. The increased level of phosphatidylinositol (4,5)-bisphosphate could be in part degraded by synaptojanin that thereby initiates the disassembly of the clathrin coat. Hence, calcium-induced transient increases in the level of phosphatidylinositol (4,5)-bisphosphate appear to play a central role for coupling exocytosis to clathrin-mediated endocytosis. In addition, it has been demonstrated that calcium also leads to the dephosphorylation of endocytic proteins as amphiphysin, dynamin, and synaptojanin, which in vitro is important for efficient coat assembly (Cousin and Robinson 2001). 

Anti-amphiphysin Amphiphysin Presynaptic vesicles Stiff-Person syndrome Breast, SCLC... 

The expression of onconeural antigens is highly restricted in some instances. Recoverin is found in the retinal cells only, and cdr2 expression is restricted to the Purkinje cells and brain stem. Other antigens such as Nova are widely distributed in the CNS, whereas the HuD and CRMP-5 antigens are expressed by neurons of both the CNS and the peripheral nervous system. The extensive immunoreactivity is reflected by the heterogenous clinical manifestations in patients with Ri, CRMP-5, Hu, and amphiphysin antibodies [15,29, 30]. 

The most common onconeural antibody in patients with PNS is Hu, followed by CRMP-5 and Yo, whereas PCA-2, amphiphysin, ANNA-2, and ANNA-3 seem to be quite rare. Apart from Yo antibody positive sera, 31% of PNS serum samples have been found to have more than one onconeural antibody, which emphasizes the importance of a broad diagnostic antibody screening [16]. 

Passive transfer of the IgG fraction from a patient with breast cancer, Stiff-Person syndrome and amphiphysin antibodies resulted in stiffness and... 

Pittock SJ, Lucchinetti CF, Parisi JE, Benarroch EE, Mokri B, Stephan CL, et al. Amphiphysin autoimmunity Paraneoplastic accompaniments. Ann Neurol 2005 58(1) 96-107. 

Wessig C, Klein R, Schneider MF, Toyka KV, Naumann M, Sommer C. Neuropathology and binding studies in anti-amphiphysin-associated stiff-person syndrome. Neurology 2003 61(2) 195-198. 

De Camilli P, Thomas A, Cofiell R, Folli F, Lichte B, Piccolo G, et al. The synaptic vesicle-associated protein amphiphysin is the 128-kD autoantigen of Stiff-Man syndrome with breast cancer. J Exp Med 1993 178(6) 2219-2223. 

Floyd S, Butler MH, Cremona O, David C, Freyberg Z, Zhang X, et al. Expression of amphiphysin I, an autoantigen of paraneoplastic neurological syndromes, in breast cancer. Mol Med 1998 4(l) 29-39. 

Sommer C, Weishaupt A, Brinkhoff J, Biko L, Wessig C, Gold R, et al. Paraneoplastic stiff-person syndrome Passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet 2005 365(9468) 1406-1411. 

Clathrin-mediated endocytosis is a major vesicular transport mechanism in the neuron, which enables the internalization of plasma membrane-bound proteins, nutrients, hormones and other molecules associated with the plasma membrane into intracellular compartments. Clathrin and various adaptor and accessory proteins work in concert at different stages of clathrin coated vesicle formation and disassembly, and many of these proteins (such as clathrin light chain, AP-2, dynamin 1, synaptojanin 1, and the amphiphysins) are substrates for protein kinases (Korolchuk et al. 2003). In addition, it has been suggested that directing synaptotagmin 1 to the synaptic vesicle is dependent on the N-terminal glycosylation of this protein (Han et al. 2004). 

Lipid demixing upon Amphiphysin BAR dimer adsorption is insufficient on its own to induce significant membrane curvatures... 

Figure 3 Steady-state shapes upon binding of the Amphiphysin N-BAR domain dimer plots show upper leaflet contours of membranes with different bending rigidities and with N-helix insertions of various depths. The membrane patches have -0.4e/nm2 average surface charge densities (corresponding to 0.3 PS lipid fractions) on both layers. The orientation of the BAR domain used in these calculations is the same as in Figure 2. For all systems, a nonzero spontaneous curvature c0 domain was defined for a membrane patch inside the BAR projection area shown in panel L and extending 20 A away from the projected zone. The values for c0 in the range of 0-1/70 A 1 were used.

Fig. 8. Effects of disruption of endophilin and amphiphysin interactions on clathrin-mediated endocytosis at the reticulospinal synapse. (A) Electron micrograph of the lateral side of the active zone in a control synapse stimulated at 5 Hz. Note the presence of clathrin-coated pits with different shapes. (B) Electron micrograph of the comparable area of a synapse in an axon that was stimulated at 5 Hz for 30 min after injection of endophilin antibodies. Note the pocket-like membrane expansions (arrows) at the margin of the synaptic area and the appearance of numerous shallow coated pits (arrows). (C) A synapse in an axon which was stimulated at 0.2 Hz for 30 min after injection of a fusion protein containing the SH3 domain of amphiphysin linked to GST. Note the accumulation of constricted coated pits around the active zone. Scale bar, 0.2 pm. B, modified from Ringstad et al. (1999), Neuron 24, 143-154, with permission copyright is held by Cell Press. C, modified from Shupliakov et al. (1997a) Science 276 259-263, with permission copyright 1997 AAAS.

Grabs, D., Slepnev, V I., Songyang, Z., David, G., Lynch, M., Cantley, L. C., and De Camilli, P. (1997). The SHS domain of amphiphysin binds the proline-rich domain of dynamin at a single site that defines a new SHS binding consensus sequence. /. Biol. Chem. 272, 13419-13425. 

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