Aberrant modulation of a delayed rectifier potassium channel by glutamate in Alzheimer's disease.
In Alzheimer's disease (AD), potassium channel abnormalities have been reported in both neural and peripheral tissues. Herein, using whole-cell patch-clamp, we demonstrate an aberrant glutamate-dependent modulation of K(V)1.3 channels in T lymphocytes of AD patients. Although intrinsic K(V)1.3 properties in patients were similar to healthy individuals, glutamate (1-1000 microM) failed to yield the hyperpolarizing shift normally observed in K(V)1.3 steady-state inactivation (-4.4+/-2.7 mV in AD vs. -14.3+/-2.5 mV in controls, 10 microM glutamate), resulting in a 4-fold increase of resting channel activity. Specific agonist and antagonist data indicate that this abnormality is due to dysfunction of cognate group II mGluRs. Given that glutamate is present in plasma and that both mGluRs and K(V)1.3 channels regulate T-lymphocyte responsiveness, our finding may account for the presence of immune-associated alterations in AD. Furthermore, if this aberration reflects a corresponding one in neural tissue, it could provide a potential target in AD pathogenesis.
Poulopoulou
Cornelia
C
Department of Neurology, Laboratory of Experimental Neurophysiology, Medical School, University of Athens, Eginition Hospital, Athens, Greece. cpoulop@med.uoa.gr
Markakis
Ioannis
I
Davaki
Panagiota
P
Tsaltas
Eleftheria
E
Rombos
Antonis
A
Hatzimanolis
Alexandros
A
Vassilopoulos
Dimitrios
D
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D020520:Brain Infarction / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D051664:Kv1.3 Potassium Channel / Q000187:drug effects / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008934:Mitogens / Q000494:pharmacology; D015213:Neuroimmunomodulation / Q000502:physiology; D018408:Patch-Clamp Techniques; D010835:Phytohemagglutinins / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D051664:Kv1.3 Potassium Channel; D008934:Mitogens; D010835:Phytohemagglutinins; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D018698:Glutamic Acid