The inhibitory adenosine A1 receptor (A1R) and excitatory A2A receptor (A2AR) are predominantly expressed in the brain. Whereas the A2AR has been implicated in normal aging and enhancing neurotoxicity in multiple neurodegenerative diseases, the inhibitory A1R has traditionally been ascribed to have a neuroprotective function in various brain insults. This review provides a summary of the emerging role of prolonged A1R signaling and its potential cross-talk with A2AR in the cellular basis for increased neurotoxicity in neurodegenerative disorders. This A1R signaling enhances A2AR-mediated neurodegeneration, and provides a platform for future development of neuroprotective agents in stroke, Parkinson’s disease and epilepsy.

Seven α-synuclein-drug complexes have been studied by nanopore analysis in which an AC field of 200 mV from 10 MHz to 1 GHz has been superimposed on the standard electrophoretic DC voltage of 100 mV. α-Synuclein has a large dipole moment and in the absence of drug the AC field causes the molecule to oscillate at the entrance to the pore and reduces its ability to translocate through the pore. Thus more bumping events are observed in the current blockade histograms. The binding of drugs to α-synuclein has a large effect on the event profiles depending on the region of α-synuclein to which the drugs bind. Caffeine and (-)-nicotine bind both the N- and C-termini causing the protein to adopt a loop conformation that allows translocation even in the AC field. Metformin, which binds only to the C-terminus also facilitates translocation. For these drugs there is good evidence that the AC field is causing the complex to dissociate as it enters the pore that has not been observed previously. In contrast, complexes with (+)-amphetamine that has an N-terminal binding site and cocaine that binds to the central region of the protein, show only small changes in the event profiles in an AC field.

In standard nanopore analysis a constant DC voltage is used to electrophoretically drive small molecules and peptides towards a pore. Superposition of an AC voltage at particular frequencies causes molecules to oscillate as they approach the pore which can alter the event parameters, the blockade current (I) and blockade time (T). Four peptides with similar structures were studied. Alpha-helical peptides A10 (FmocDDA10KK), A14, A18 and retro-inverso A10. It was shown that the ratio of translocations to bumping events could be manipulated by a combination of AC voltages and frequencies. In particular, A10 could be studied without interference from retro-inverso A10. Similarly, a large, intrinsically disordered protein of 140 amino acids, α-synuclein, which translocates the pore readily in a DC field could be prevented from doing so by application of an AC field of 200 mV at 100 MHz.