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Chaudhry group
Transport & recycling of
neurotransmitters & amino acids
Group leader: Dr. med. Farrukh
A. Chaudhry
Research Aims:
to unravel functional mechanisms
of transporter proteins involved in the translocation of amino acids across
membranes, and their physiological and pathophysiological roles (e.g. in
neurotransmitter recycling, epilepsy, neoplasia), as well as to identify their
potentials as therapeutic targets.
Background and recent research
activities:
The glutamate/GABA-glutamine cycle: Glutamine has
for more than 30 years been regarded as the precursor compound for the
production of glutamate and GABA, which are the most important stimulatory and
inhibitory signal transmitters, respectively, in the brain. It is assumed that
glutamate and GABA released in the synapses are taken up into the surrounding
glial cells and converted to glutamine which is then transported back to the
nerve cells. This recycling and reproduction of signal substance is necessary
in order to maintain signal transduction in the brain.
Glutamine:
Glutamine is also a crucial compound in general metabolism. It is the most
abundant free amino acid in plasma, cerebrospinal fluid and brain extracellular
space. It plays a critical role in nitrogen metabolism, detoxification of
ammonia and production of urea, and in the formation of amino acids, amino
sugars, purines and pyrimidines. During chronic metabolic acidosis (CMA), the
plasma levels of glutamine are increased and so is glutamine metabolism in the
kidney tubule cells. Degradation of glutamine results in the formation of
ammonium (NH4+) and bicarbonate (HCO3-) ions, which are excreted in the
preurine and transported to the peritubular blood. This process contributes to
counteract acidosis and to restore normal pH. But the molecular mechanism, the
localization of the proteins involved and the regulation of glutamine transport
e.g. in the CNS and in the kidney have remained unknown.
Transporter
proteins: Transporters are integral membrane proteins characterized by
their ability to mediate transmembrane movement of small hydrophilic molecules
against their concentration gradients. Two activities are identified: One
activity exists at the plasma membrane energized by e.g. co-transport of Na+,
and one at the synaptic vesicles dependent on H+ counter-transport. Members of
our group have contributed to the characterization of a novel family of amino
acid transporters able to transport the amino acid glutamine through the cell
membrane. (Chaudhry et al., Cell, 1999; Reimer, Chaudhry et al., PNAS, 2000;
Chaudhry et al., EMBO J, 2001; Chaudhry et al., J Neurosci, 2002; Chaudhry et
al.; for review J Cell Biol, 2002).
Different coupling to Na+ and H+ causes
SN1 and SN2 to release glutamine from the cells, while SAT1 and SAT2 transport
glutamine into the cells against a concentration gradient. We have shown that
SN1 and SN2 are expressed in glia whereas SAT1 and SAT2 are expressed in
neurons, implicating their roles in the glutamate/GABA-glutamine cycle.
Furthermore, sorting of SN1 to the basolateral membranes of tubule cells and
the presence of a putative pH responsive element in the 3' untranslated region
(UTR) are conducive to the function of this transporter in pH regulation.
In addition, we have also characterized other transporters, such as several
vesicular transporter proteins (Chaudhry et al., J Neurosci, 1998; Fremeau et
al., PNAS, 2002; Fremeau et al., Science, 2004). Finally, we have shown the
localization of various transporters by high resolution immunocytochemical
techniques, such as immunogold electron microscopy (Chaudhry et al., Neuron,
1995; Dehnes et al., J Neurosci, 1998; Mason et al., Eur J Neurosci, 1998;
Boulland et al., Eur J Neurosci, 2002; Boulland et al., J Comp Neur,
2004).
Future research:
Focus on understanding the basic
properties of these transporters and to explore their role at physiological and
pathological conditions by means of molecular biological, electrophysiological
and immunocytochemical/immunogold light and electron microscopic
techniques.
Attachment:
Chaudhry's group is also associated
to the Centre for Molecular Biology and Neuroscience
(http://www.cmbn.uio.no/about.html).
Publications
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here to go to list of publications
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