Function of D15 As An Endocytosis Inhibitor

2018-10-09

Introduction 

The endocytosis of AMPA receptors (AMPARs) requires the GTPase activity of dynamin. Since it is now established that a common mechanism for the stimulation of dynamin GTPase activity involves the promotion or stabilization of GDP and gamma phosphate-dependent self-assembly of dynamin, we loaded cells with the inhibitor GDPβS. This manipulation caused a slowly developing enhancement of the AMPAR excitatory postsynaptic currents (EPSC) that reached a magnitude of greater than 2-fold. In striking contrast, the NMDAR EPSC was unaffected by this manipulation. While the effect of GDPβS was dramatic, a limitation of this manipulation is that GTPase activity is involved in a number of cellular processes, including exocytosis. The amino acid sequence of D15 is PPPQVPSRPNRAPPG. The 15-amino acid peptide used to disrupt dynamin's interaction with amphiphysin, D15 can rapidly enhance the AMPAR EPSC and block endocytosis more selectively, which is known to interfere with the binding of amphiphysin with dynamin, an interaction that is considered important for endocytosis to occur.

Pharmacologic action

The 15–amino acid peptide (D15) that prevents the interaction between amphiphysin and dynamin, an interaction that is required for endocytosis. Injection of D15, but not a scrambled version of the peptide, led to a rapid increase in the AMPAR EPSC, but no change in the NMDAR EPSC. Synaptic AMPARs do in fact undergo a constitutive endocytosis, which functions to limit the number of AMPARs in the PSD. Furthermore, the AMPA-induced translocation of surface AMPARs to internal sites is blocked by expressing D15 in cultured neurons.

Function

AMPARs undergo dynamin-dependent endocytosis. If endocytosis also occurs constitutively and affects functional AMPARs at the synapse, blockade of endocytosis would be expected to result in an accumulation of surface AMPARs and thereby an increase in the AMPAR EPSC. Blockade of GTP-dependent processes, which are required for endocytosis, with the application of GDPβS resulted in a significant but delayed increase in the AMPAR EPSC. The NMDAR EPSC was unaffected by this manipulation. While this result is in accord with a blockade of constitutive endocytosis, many cellular processes are dependent on GTP hydrolysis. The depressant action of G10 required synaptic stimulation, while the actions of Botox, GDPβS, and D15 did not.

References:

Beattie E C. Role of AMPA receptor cycling in synaptic transmission and plasticity.[J]. Neuron, 1999, 24(3):649-658.

Xiao M Y, Zhou Q, Nicoll R A. Metabotropic glutamate receptor activation causes a rapid redistribution of AMPA receptors [J]. Neuropharmacology, 2001, 41(6):664-671.

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