Blocking L-type voltage-gated Ca2+ channels with dihydropyridines reduces gamma-aminobutyric acid type A receptor expression and synaptic inhibition.
Gamma-aminobutyric acid type A receptors (GABA(A)Rs) are the major sites of fast inhibitory neurotransmission in the brain, and the numbers of these receptors at the cell surface can determine the strength of GABAergic neurotransmission. Chronic changes in neuronal activity lead to an adaptive modulation in the efficacy of GABAergic synaptic inhibition, brought about in part by changes in the number of synaptic GABA(A)Rs, a mechanism known as homeostatic synaptic plasticity. Reduction in the number of GABA(A)Rs in response to prolonged neuronal activity blockade is dependent on the ubiquitin-proteasome system. The underlying biochemical pathways linking chronic activity blockade to proteasome-dependent degradation of GABA(A)Rs are unknown. Here, we show that chronic blockade of L-type voltage-gated calcium channels (VGCCs) with nifedipine decreases the number of GABA(A)Rs at synaptic sites but not the overall number of inhibitory synapses. In parallel, blockade of L-type VGCCs decreases the amplitude but not the frequency of miniature inhibitory postsynaptic currents or expression of the glutamic acid decarboxylase GAD65. We further reveal that the activation of L-type VGCCs regulates the turnover of newly translated GABA(A)R subunits in a mechanism dependent upon the activity of the proteasome and thus regulates GABA(A)R insertion into the plasma membrane. Together, these observations suggest that activation of L-type VGCCs can regulate the abundance of synaptic GABA(A)Rs and the efficacy of synaptic inhibition, revealing a potential mechanism underlying the homeostatic adaptation of fast GABAergic inhibition to prolonged changes in activity.
Department of Neuroscience, Tufts University, Boston, Massachusetts 02111, USA.
Richard S
RS
Saliba
Zhenglin
Z
Gu
Zhen
Z
Yan
Stephen J
SJ
Moss
D000818:Animals; D019921:Biotinylation; D002121:Calcium Channel Blockers / Q000737:chemistry*; D020746:Calcium Channels, L-Type / Q000737:chemistry*; D004095:Dihydropyridines / Q000494:pharmacology*; D005786:Gene Expression Regulation; D005968:Glutamate Decarboxylase / Q000737:chemistry; D006624:Hippocampus / Q000196:embryology / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D018079:Receptors, GABA / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects*; D025801:Ubiquitin / Q000737:chemistry
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D018079:Receptors, GABA; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2