Normal 0 0 2 false false false EN-US ZH-TW X-NONE st1\:*{behavior:url(#ieooui) } /* Style Definitions */ table.MsoNormalTable {mso-style-name:表格內文; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Calibri",sans-serif; mso-bidi-font-family:"Times New Roman";} Voltage-gated P/Q-type calcium (CaV2.1) channels critically regulate synaptic signaling in the nervous system. Loss-of-function mutations in the human gene encoding the pore-forming α1A (CaV2.1) subunit are linked to the cerebellar disease episodic ataxia type 2 (EA2). Several EA2-causing CaV2.1 mutant subunits are associated with enhanced proteasomal degradation and may exert dominant-negative suppression of the protein homeostasis of their wild-type (WT) counterpart. We reported previously that the E3 ubiquitin ligase RNF138 promotes polyubiquitination and proteasomal degradation of CaV2.1, as well as mediating EA2-associated aberrant protein homeostasis of CaV2.1. To further elucidate the molecular mechanism underlying CaV2.1 regulation by RNF138, herein we investigated the role of a peptidyl-prolyl cis/trans isomerase (PPIase) in controlling CaV2.1 protein homeostasis. We demonstrated that the PPIase was a novel Cav2.1-binding partner and colocalized with CaV2.1 subunit in both presynaptic and postsynaptic compartments in neurons. Like RNF138, the PPIase effectively promoted polyubiquitination and proteasomal degradation of CaV2.1. Also like RNF138, the PPIase contributed to defective protein homeostasis of EA2-causing CaV2.1 nonsense and missense mutants. We further identified two protein domains within CaV2.1 that were essential for its interaction with the PPIase. Importantly, selective mutations in the two PPIase-interacting protein domains rendered the mutant CaV2.1 insensitive to protein degradation by both the PPIase and RNF138, suggesting that the PPIase may serve as an upstream regulator of CaV2.1-RNF138 interaction. We are currently studying whether the PPIase may also be involved in the dominant-negative effect of EA2-causing mutants on WT CaV2.1 protein homeostasis.