Caulino-Rocha Ana, Rodrigues Nádia Carolina, Ribeiro Joaquim Alexandre, Cunha-Reis Diana
Departamento de Química e Bioquímica Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal.
BioISI-Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal.
Biology (Basel). 2022 Apr 20;11(5):627. doi: 10.3390/biology11050627.
Vasoactive intestinal peptide (VIP), acting on both VPAC and VPAC receptors, is a key modulator of hippocampal synaptic transmission, pyramidal cell excitability and long-term depression (LTD), exerting its effects partly through modulation GABAergic disinhibitory circuits. Yet, the role of endogenous VIP and its receptors in modulation of hippocampal LTP and the involvement of disinhibition in this modulation have scarcely been investigated. We studied the modulation of CA1 LTP induced by TBS via endogenous VIP release in hippocampal slices from young-adult Wistar rats using selective VPAC and VPAC receptor antagonists, evaluating its consequence for the phosphorylation of CamKII, GluA1 AMPA receptor subunits and Kv4.2 potassium channels in total hippocampal membranes obtained from TBS stimulated slices. Endogenous VIP, acting on VPAC (but not VPAC) receptors, inhibited CA1 hippocampal LTP induced by TBS in young adult Wistar rats and this effect was dependent on GABAergic transmission and relied on the integrity of NMDA and CaMKII-dependent LTP expression mechanisms but not on PKA and PKC activity. Furthermore, it regulated the autophosphorylation of CaMKII and the expression and Ser phosphorylation of Kv4.2 potassium channels responsible for the A-current while inhibiting phosphorylation of Kv4.2 on Thr. Altogether, this suggests that endogenous VIP controls the expression of hippocampal CA1 LTP by regulating disinhibition through activation of VPAC receptors in interneurons. This may impact the autophosphorylation of CaMKII during LTP, as well as the expression and phosphorylation of Kv4.2 K channels at hippocampal pyramidal cell dendrites.
血管活性肠肽（VIP）作用于VPAC₁和VPAC₂受体，是海马突触传递、锥体细胞兴奋性和长时程抑制（LTD）的关键调节因子，其部分作用是通过调节GABA能去抑制回路来实现的。然而，内源性VIP及其受体在调节海马长时程增强（LTP）中的作用以及去抑制在这种调节中的参与情况几乎未被研究过。我们使用选择性VPAC₁和VPAC₂受体拮抗剂，研究了成年Wistar大鼠海马切片中内源性VIP释放对强直刺激（TBS）诱导的CA₁区LTP的调节作用，并评估了其对从TBS刺激切片中获得的全海马膜中钙/钙调蛋白依赖性蛋白激酶II（CamKII）、谷氨酸受体A1（GluA1）亚基和钾通道蛋白4.2（Kv4.2）磷酸化的影响。内源性VIP作用于VPAC₁（而非VPAC₂）受体，抑制成年Wistar大鼠TBS诱导的CA₁海马LTP，这种作用依赖于GABA能传递，且依赖于N-甲基-D-天冬氨酸（NMDA）和CaMKII依赖性LTP表达机制的完整性，但不依赖于蛋白激酶A（PKA）和蛋白激酶C（PKC）的活性。此外，它调节CaMKII的自磷酸化以及负责A电流的Kv4.2钾通道的表达和丝氨酸磷酸化，同时抑制Kv4.2苏氨酸位点的磷酸化。总之，这表明内源性VIP通过激活中间神经元中的VPAC₁受体来调节去抑制，从而控制海马CA₁区LTP的表达。这可能会影响LTP期间CaMKII的自磷酸化，以及海马锥体细胞树突处Kv4.2钾通道的表达和磷酸化。
