Disruption of polycystin-L causes hippocampal and thalamocortical hyperexcitability

Abstract

Epilepsy or seizure disorder is among the least understood chronic medical conditions affecting over 65 million people worldwide. Here, we show that disruption of the polycystic kidney disease 2-like 1 (Pkd2l1 or Pkdl), encoding polycystin-L (PCL), a non-selective cation channel, increases neuronal excitability and the susceptibility to pentylenetetrazol-induced seizure in mice. PCL interacts with β2-adrenergic receptor (β2AR) and co-localizes with β2AR on the primary cilia of neurons in the brain. Pkdl deficiency leads to the loss of β2AR on neuronal cilia, which is accompanied with a remarkable reduction in cAMP levels in the central nervous system (CNS). The reduction of cAMP levels is associated with a reduction in the activation of cAMP response element-binding protein, but not the activation of Ca(2+)/calmodulin-dependent protein kinase II, Akt or mitogen-activated protein kinases. Our data, thus, indicate for the first time that a ciliary protein complex is required for the control of neuronal excitability in the CNS.

SoxB1 Activity Regulates Sensory Neuron Regeneration, Maintenance, and Function in Planarians

“…Polycystin-L (PCL), a Ca 2+ -permeable channel encoded by PKD2-like 1 and related to Polycystin 2, is expressed in the primary cilia of neuronal cells of the brain and its loss of function leads to decreased cyclic AMP production and neuronal excitability (Gross and Ferrendelli, 1979). Yao et al (2016) showed that loss of PCL causes increased neuronal hyperexcitability and susceptibility to seizures in mice, thus implicating primary cilia in EDs. Our findings point to a conserved function of PKD genes in cilia-mediated signaling of neurons and in seizure-like disorders.…”

Regulation of TRPP3 Channel Function by N-terminal Domain Palmitoylation and Phosphorylation

“…TRPP3 is expressed in the brain (14), and a recent study using TRPP3 knock-out mice found that disruption of TRPP3 causes hippocampal and thalamocortical hyperexcitability and increases susceptibility to pentylenetetrazol-induced seizures (47). Interestingly, several neural proteins, including various G-protein-coupled receptors and ion channels that control the excitability of neurons, have now been reported to be dynamically regulated by palmitoylation (48).…”

“…It would be interesting to see whether palmitoylation of TRPP3 at Cys-38 represents a mechanism underlying the control of TRPP3 channel activity in neurons with respect to neuronal excitability. TRPP3 was also found to interact with ␤2-adrenoreceptor (␤2AR) and co-localize with ␤2AR in the brain (47). Binding of agonist isoproterenol to ␤2AR was reported to markedly reduce the palmitoylation of the associated G␣ s (49).…”

Calcium channels in primary cilia

“…TRPP3, also called polycystin-L (PKDL) or polycystin-2L1 (PKD2L1), is localized to primary cilia (53, 66) and the centrosome (67). TRPP3 is a calcium channel with a high homology with TRPP2 (68).…”

“…A very recent study by Zhou's group indicates that TRPP3 in the neuronal primary cilium regulates neuronal excitability and susceptibility to pentylenetetrazol-induced seizure in mice (66). The group showed that TRPP3 interacts with the β2 adrenergic receptor and that the receptor-channel complex regulates cAMP response element-binding protein.…”