Page - (000277) - in Biomedical Chemistry: Current Trends and Developments

trafficking plays a crucial role in synaptic plasticity, which, in turn, is believed to underlie memory formation and loss. 3.2.2.1 AMPA Receptors AMPA receptors are assembled from subunits GluA1 through GluA4 and are typically comprised of heterotetramers, quite often containing GluA2 subunits. These receptors are known to play a critical role in long-term potentiation (LTP), one of the mechanisms thought to underlie memory formation as well as maladaptive and even neurodegenerative plasticity (Kang, 2009). Most AMPA receptors are not permeable to calcium ions, due to the presence of the GluA2 subunit. In the GluA2 subunit RNA, a key modification is made to translate a codon to arginine instead of a glutamine in the ion channel pore. The incorporation of arginine in the ion conduction pore results in a channel that does not allow divalent cations, such as calcium, to pass. A subset of AMPA receptors that are currently of considerable interest in the neurobiology field and in particular the field of neurodegeneration are those that lack the GluA2 subunit. GluA2- containing channels are quite often calcium-impermeable due to an mRNA codon editing event (Araki, 2010; Isaac, 2007). The precise role of GluA2-lacking receptors in synaptic plasticity or, for that matter, normal synaptic signaling, is still the subject of ongoing debate in the field (Henley, 2011). While it is thought that most functional AMPA receptors contain an edited GluA2 subunit, there is now considerable evidence for a subpopulation of GluA2-lacking receptors that result in calcium- permeable AMPA receptors (Keller, 1992; McDermott, 2003; Szabo, 2012; Wright & Vissel, 2012). The enzyme Adenosine deaminase acting on RNA 2 (ADAR2) specifically mediates RNA editing of the glutamine/arginine (Q/R) site of GluA2 subunit of the AMPA receptors and it has been found that motor neurons expressing Q/R site-unedited GluA2 undergo slow death in conditional ADAR2 knockout mice (Hideyama, 2012). This line of research also found that unedited GluA2 mRNA was expressed in a large proportion of motor neurons from ALS patients while motor neurons from normal and disease control subjects expressed only edited GluA2 mRNA. ADAR2 was significantly down-regulated in all the motor