Kari Keinänen - Biochemistry and Biotechnology

Molecular Biology of AMPA Receptors

Professor Kari Keinänen, PhD

AMPA receptors are named after a selective agonist, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. They are transmembrane ion channels which open transiently upon binding of glutamate, passing cations through the plasma membrane. In the brain, AMPA receptors mediate excitatory synaptic neurotransmission, but may also, under pathological conditions, contribute to glutamate-induced neuronal death.

 

Regulation of the number, spatial distribution, and biophysical properties of AMPA receptors is believed to be one of the major mechanisms by which experience or developmental stimuli can impart  changes in synaptic strength. Our research, motivated by the central importance of these phenomena to neuronal function, focuses on molecular level analysis of AMPA receptors and their interactions with other molecules.

 

Our specific research interests are listed below:

1. Assembly of the receptor

AMPA receptors are tetramers built from a pool of four subunits, GluR-A, -B, -C, and -D (or GluR1-4), each of which may exist as multiple molecular variants due to RNA splicing and editing. The functional properties of AMPA receptors depend on subunit composition, which also determines the molecular interactions  mediating receptor trafficking to and from synapses.

Our goal is to identify the structural mechanisms which regulate the assembly of homomeric and heteromeric AMPA receptors.

2. Receptor trafficking

Important forms of developmental and use-dependent synaptic plasticity specifically involve AMPA receptors with GluR-A and GluR-D subunits. We are analyzing the molecular interactions of these subunits with multidomain scaffolding proteins SAP97 and 4.1N in order to determine the structural basis of these interactions and their role in selective receptor trafficking.

3. Extracellular interactions

We and others have shown that the extracellular domain of AMPA receptor consists of two relatively independent parts, a bipartite ligand -binding domain ("S1S2") which is tightly coupled to transmembrane ion channel, and a large, evolutionarily conserved N-terminal segment, "X domain". Our previous studies indicate that this domain is dispensable for ligand-gated ion channel function. We are interested in assigning a functional role for this domain, likely to be involved in extracellular synaptic interactions.

We use a variety of molecular biological, biochemical and cell biological methods, and work in close collaboration with biophysicists and neurophysiologists both in Finland and abroad.