Abstract
The protein kinase Csnk2/CK2 is important for cell proliferation, differentiation, and survival. Previously, we showed that CK2 binds distinctive proteins at neuromuscular junctions (NMJs) of mice and phosphorylates some of them. CK2 likely stabilizes clustered nicotinic acetylcholine receptors (AChRs). In the absence of the β-subunit of CK2 in skeletal muscle fibers, mice develop an age-dependent decrease of grip strength accompanied by NMJ fragmentation and impairments of neuromuscular transmission. However, the precise role of CK2β regarding the clustering of AChRs and downstream signaling at NMJs is unknown. Here, we compared conditional CK2β-deficient mice with controls and found in the mutants (1) a lower decrement of endplate potentials after repetitive stimulation and decrements of nerve-evoked compound muscle action potentials decayed more rapidly after synaptic transmission was partially blocked, (2) that their muscle weakness was partially rescued by administration of an acetylcholine esterase inhibitor, (3) fragmented NMJs and impaired AChR clustering was detected in muscles and cultured muscle cells, (4) enlarged myonuclei, (5) impaired synaptic gene expression, and (6) a high turnover rate of their AChR clusters in vivo. Altogether, our data demonstrate a role for CK2 at the NMJ by maintaining a high density of AChRs and ensuring physiological synaptic gene expression.
Highlights
The neuromuscular junction (NMJ) is a prototypical large synapse and the point of contact between motor nerve endings and a specialized surface area of muscle fibers [1]
We recorded a difference of miniature endplate current amplitudes by comparing diaphragm muscle fibers of conditional CK2β-deficient and control mice, especially opposing control muscle fibers with regular NMJs with mutant fibers and structurally fragmented NMJs [8,16]
In order to better understand the properties of neuromuscular transmission in the CK2β-deficient mice, we measured a number of electrophysiological parameters in CK2β-deficient mutant diaphragm fibers with fragmented NMJs and control muscle fibers with unaffected NMJs
Summary
The neuromuscular junction (NMJ) is a prototypical large synapse and the point of contact between motor nerve endings and a specialized surface area of muscle fibers [1]. Pre- and postsynaptic signaling pathways are mandatory for the formation and the maintenance of NMJs, and neuromuscular transmission is needed for muscle contraction. Motor nerve derived isoforms of a large heparan sulfate proteoglycoprotein called agrin are mandatory for NMJ formation and initiate a signaling cascade through interaction with their receptor Lrp on the surface of muscle fibers [2,3,4]. The receptor tyrosine kinase MuSK, part of a co-receptor with Lrp, becomes active and ensures both clustering of. Several intracellular MuSK binding proteins have been discovered in recent decades, helping us to understand the signals necessary to build and maintain
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