Corticosteroid regulation of ion channel conductances and mRNA levels in individual hippocampal CA1 neurons.
Overexposure to corticosteroid hormones is harmful to hippocampal neuronal integrity, likely by perturbation of calcium homeostasis. To identify molecular mechanisms at the single-cell level, we characterized mRNA expression corresponding to voltage- and ligand-gated Ca channels in individual dissociated CA1 neurons in response to long-term corticosterone (CORT) exposure. Predominant mineralocorticoid receptor occupation (ADC-LO group) resulted in low levels of P/Q- and L-type Ca channel mRNAs, high levels of GluR-2 versus GluR-1, and a high ratio of NMDAR-2A to NMDAR-2B mRNA. Corresponding alterations in protein expression were consistent with the restriction of Ca influx. In contrast, additional glucocorticoid receptor occupation (ADC-HI group) altered the expression of these mRNAs in a manner consistent with enhanced Ca influx; interestingly, qualitatively similar alterations were seen in control ADX neurons. Electrophysiological data from the same neurons indicate that Ca current amplitudes also are modulated by CORT, although on a shorter time scale. Finally, principal components analysis (PCA) suggests that neuronal AMPA and NMDA receptor composition may be regulated by MR and GR activation in a complex manner. Therefore, our data implicate molecular events by which CORT may regulate Ca influx into CA1 hippocampal neurons.
Nair
S M
SM
Department of Pharmacology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA.
Werkman
T R
TR
Craig
J
J
Finnell
R
R
Joëls
M
M
Eberwine
J H
JH
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000315:Adrenalectomy; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology*; D015640:Ion Channel Gating / Q000502:physiology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism
D000305:Adrenal Cortex Hormones; D015220:Calcium Channels; D012333:RNA, Messenger; D018091:Receptors, AMPA; D011965:Receptors, Glucocorticoid; D016194:Receptors, N-Methyl-D-Aspartate; D002118:Calcium