GABAB receptor phosphorylation regulates KCTD12-induced K⁺ current desensitization.
Bottom Line: Receptor-activated K(+) currents desensitize in the sustained presence of agonist to avoid excessive effects on neuronal activity.GABAB receptor activity reduces protein kinase-A activity, which reduces phosphorylation of serine-892 in GABAB2 and promotes receptor degradation.This cross-regulation of serine-892 phosphorylation and KCTD12 activity sharpens the response during repeated receptor activation.
Affiliation: Department of Biomedicine, University of Basel, 4056 Basel, Switzerland.Show MeSH
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Mentions: We next investigated whether PKA modulates the desensitization of GABAB-activated K+ currents in cultured hippocampal neurons, which are known to express KCTD12 [18,19,23]. With WT neurons, K+ currents elicited by 60-s long applications of baclofen showed a steady-state desensitization of 53.3 ±9.3% (n = 41, Fig. 4A). The time course of desensitization was approximated by a double exponential function with time constants of 1.5 ± 0.3 s (τ1) and 24.4 ± 6.4 s (τ2) (Fig. 4B), values that are similar as in earlier experiments [18,19]. Activation of PKA with 8-Br-cAMP or forskolin significantly increased the fast component τ1 of the desensitization, while inhibition of PKA with H89 or PKI had the opposite effect (Fig. 4B). Neither activation nor inhibition of PKA had a significant effect on the slow component τ2 of the desensitization (Fig. 4B). The relative contribution of the fast and slow components (τ1 and τ2, respectively) to the desensitization did not change with any of the treatments (τ1 of control: 46.5 ±10.0%; cAMP: 36.3 ±15.4%; FSK: 40.3 ±17.8%; H89: 55.7 ± 12.2%; PKI: 47.7 ± 7.7%; p>0.05; Dun-nett’s multiple comparison test). These results reveal that PKA activity specifically influences the fast component of baclofen-induced K+ current desensitization in WT neurons.
Affiliation: Department of Biomedicine, University of Basel, 4056 Basel, Switzerland.