Modulating modulation: crosstalk between regulatory pathways of presynaptic calcium channels.
The activity of some voltage-gated calcium channels (VGCCs) can be inhibited by specific G protein beta subunits. Conversely, in the case of N-type VGCCs, protein kinase C can relieve Gbeta-dependent inhibition by phosphorylating at least one specific site on the calcium channel. A recent publication describes a newly identified method of intracellular regulation of specific VGCCs. Wu et al. have uncovered that VGCC activity can be regulated by phosphatidylinositol-4',5'-bisphosphate (PIP2). Whereas PIP2 is important for maintaining the activity (open state) of Cav2.1 (N-type) and Cav2.2 (P/Q-type) channels, the enzymatic breakdown of PIP2 leads to the inactivation of these channels. Additionally, PIP2 can cause changes in voltage-dependent activation of Cav2.2 (P/Q-type) channels that make it more difficult for these channels to open (from the closed state). Furthermore, protein kinase A activity can circumvent PIP2-mediated inhibition. Thus, the PIP2-mediated regulation of VGCCs is tightly controlled by the functions of kinases (and phosphatases), as well as phospholipases. Wu et al. stress that because PIP2 can be found at synapses, PIP2-dependent control of VGCCs "could have profound consequences on synaptic transmission and plasticity."
Zamponi
Gerald W
GW
Department of Physiology and Biophysics, University of Calgary, Canada. zamponi@ucalgary.ca
Snutch
Terrance P
TP
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D004594:Electrophysiology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D011493:Protein Kinase C; D019204:GTP-Binding Proteins