Neurological phenotype and synaptic function in mice lacking the CaV1.3 alpha subunit of neuronal L-type voltage-dependent Ca2+ channels.
Neuronal L-type calcium channels have been implicated in pain perception and neuronal synaptic plasticity. To investigate this we have examined the effect of disrupting the gene encoding the CaV1.3 (alpha 1D) alpha subunit of L-type Ca2+ channels on neurological function, acute nociceptive behavior, and hippocampal synaptic function in mice. CaV1.3 alpha 1 subunit knockout (CaV1.3 alpha 1(-/-)) mice had relatively normal neurological function with the exception of reduced auditory evoked behavioral responses and lower body weight. Baseline thermal and mechanical thresholds were unaltered in these animals. CaV1.3 alpha 1(-/-) mice were also examined for differences in N-methyl-D-aspartate (NMDA) receptor-dependent (100 Hz tetanization for 1 s) and NMDA receptor-independent (200 Hz in 100 microM DL-2-amino-5-phosphopentanoic acid) long-term potentiation within the CA1 region of the hippocampus. Both NMDA receptor-dependent and NMDA receptor-independent forms of long-term potentiation were expressed normally. Radioligand binding studies revealed that the density of (+)[3H]isradipine binding sites in brain homogenates was reduced by 20-25% in CaV1.3 alpha 1(-/-) mice, without any detectable change in CaV1.2 (alpha 1C) protein levels as detected using Western blot analysis. Taken together these data indicate that following loss of CaV1.3 alpha 1 subunit expression there is sufficient residual activity of other Ca2+ channel subtypes to support NMDA receptor-independent long-term potentiation and some forms of sensory behavior/function.
Clark
N C
NC
The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.
Nagano
N
N
Kuenzi
F M
FM
Jarolimek
W
W
Huber
I
I
Walter
D
D
Wietzorrek
G
G
Boyce
S
S
Kullmann
D M
DM
Striessnig
J
J
Seabrook
G R
GR
D000818:Animals; D001522:Behavior, Animal; D001665:Binding Sites; D001835:Body Weight; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics; D015220:Calcium Channels; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016022:Case-Control Studies; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004326:Drinking; D004423:Ear / Q000502:physiology; D004435:Eating; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007553:Isotope Labeling / Q000379:methods; D017275:Isradipine / Q000493:pharmacokinetics; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D009474:Neurons / Q000502:physiology*; D015345:Oligonucleotide Probes; D017288:Pain Threshold; D010641:Phenotype; D051381:Rats; D012399:Rotation; D013569:Synapses / Q000502:physiology*; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D003838:Deoxyadenine Nucleotides; D015345:Oligonucleotide Probes; C093712:Cacna1d protein, rat; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine; C026600:2'-deoxyadenosine triphosphate; D017275:Isradipine