Presenilin 1 deficiency alters the activity of voltage-gated Ca2+ channels in cultured cortical neurons.
Presenilins 1 and 2 (PS1 and PS2, respectively) play a critical role in mediating gamma-secretase cleavage of the amyloid precursor protein (APP). Numerous mutations in the presenilins are known to cause early-onset familial Alzheimer's disease (FAD). In addition, it is well established that PS1 deficiency leads to altered intracellular Ca(2+) homeostasis involving endoplasmic reticulum Ca(2+) stores. However, there has been little evidence suggesting Ca(2+) signals from extracellular sources are influenced by PS1. Here we report that the Ca(2+) currents carried by voltage-dependent Ca(2+) channels are increased in PS1-deficient cortical neurons. This increase is mediated by a significant increase in the contributions of L- and P-type Ca(2+) channels to the total voltage-mediated Ca(2+) conductance in PS1 (-/-) neurons. In addition, chelating intracellular Ca(2+) with 1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) produced an increase in Ca(2+) current amplitude that was comparable to the increase caused by PS1 deficiency. In contrast to this, BAPTA had no effect on voltage-dependent Ca(2+) conductances in PS1-deficient neurons. These data suggest that PS1 deficiency may influence voltage-gated Ca(2+) channel function by means that involve intracellular Ca(2+) signaling. These findings reveal that PS1 functions at multiple levels to regulate and stabilize intracellular Ca(2+) levels that ultimately control neuronal firing behavior and influence synaptic transmission.
Cook
David G
DG
Veterans Affairs Puget Sound Health Care System, Geriatric Research Education and Clinical Center (GRECC), Seattle, Washington, USA.
Li
Xiaofan
X
Cherry
Sheree D
SD
Cantrell
Angela R
AR
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000145:classification / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D002614:Chelating Agents / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004553:Electric Conductivity; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D053764:Presenilin-1
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002614:Chelating Agents; D008565:Membrane Proteins; D010726:Phosphodiesterase Inhibitors; D053764:Presenilin-1; D002110:Caffeine; D004533:Egtazic Acid; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid