1 Pancreatic oedema occurs early in the development of acute pancreatitis, and the overall extent of¯uid loss correlates with disease severity. The tachykinin substance P (SP) is released from sensory nerves, binds to the neurokinin-1 receptor (NK1-R) on endothelial cells and induces plasma extravasation, oedema, and neutrophil in®ltration, a process termed neurogenic in¯ammation. We sought to determine the importance of neurogenic mechanisms in acute pancreatitis. 2 Pancreatic plasma extravasation was measured using the intravascular tracers Evans blue and Monastral blue after administration of speci®c NK1-R agonists/antagonists in rats and NK1-R(+/ +)/(7/7) mice. The eects of NK1-R genetic deletion/antagonism on pancreatic plasma extravasation, amylase, myeloperoxidase (MPO), and histology in cerulein-induced pancreatitis were characterized. 3 In rats, both SP and the NK1-R selective agonist [Sar 9 Met(O 2 ) 11]SP stimulated pancreatic plasma extravasation, and this response was blocked by the NK1-R antagonist CP 96,345. Selective agonists of the NK-2 or NK-3 receptors had no eect. 4 In rats, cerulein stimulated pancreatic plasma extravasation and serum amylase. These responses were blocked by the NK1-R antagonist CP 96,345. 5 In wildtype mice, SP induced plasma extravasation while SP had no eect in NK1-R knockout mice. 6 In NK1-R knockout mice, the eects of cerulein on pancreatic plasma extravasation and hyperamylasemia were reduced by 60%, and pancreatic MPO by 75%, as compared to wildtype animals. 7 Neurogenic mechanisms of in¯ammation are important in the development of in¯ammatory oedema in acute interstitial pancreatitis.

KCNQ potassium channels composed of KCNQ2 and KCNQ3 subunits give rise to the M-current, a slow-activating and non-inactivating voltage-dependent potassium current that limits repetitive firing of action potentials. KCNQ channels are enriched at the surface of axons and axonal initial segments, the sites for action potential generation and modulation. Their enrichment at the axonal surface is impaired by mutations in KCNQ2 carboxy-terminal tail that cause benign familial neonatal convulsion and myokymia, suggesting that their correct surface distribution and density at the axon is crucial for control of neuronal excitability. However, the molecular mechanisms responsible for regulating enrichment of KCNQ channels at the neuronal axon remain elusive. Here, we show that enrichment of KCNQ channels at the axonal surface of dissociated rat hippocampal cultured neurons is regulated by ubiquitous calcium sensor calmodulin. Using immunocytochemistry and the cluster of differentiation 4 (CD4) membrane protein as a trafficking reporter, we demonstrate that fusion of KCNQ2 carboxy-terminal tail is sufficient to target CD4 protein to the axonal surface whereas inhibition of calmodulin binding to KCNQ2 abolishes axonal surface expression of CD4 fusion proteins by retaining them in the endoplasmic reticulum. Disruption of calmodulin binding to KCNQ2 also impairs enrichment of heteromeric KCNQ2/KCNQ3 channels at the axonal surface by blocking their trafficking from the endoplasmic reticulum to the axon. Consistently, hippocampal neuronal excitability is dampened by transient expression of wild-type KCNQ2 but not mutant KCNQ2 deficient in calmodulin binding. Furthermore, coexpression of mutant calmodulin, which can interact with KCNQ2/KCNQ3 channels but not calcium, reduces but does not abolish their enrichment at the axonal surface, suggesting that apo calmodulin but not calcium-bound calmodulin is necessary for their preferential targeting to the axonal surface. These findings collectively reveal calmodulin as a critical player that modulates trafficking and enrichment of KCNQ channels at the neuronal axon.

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Persistent inward currents (PICs) are responsible for amplifying motoneuronal synaptic inputs and contribute to generating normal motoneuron activation. Delta-F (∆F) is a well-established method which estimates PICs in humans indirectly from firing patterns of individual motor units. Traditionally, motor unit firing patterns are obtained by manually decomposing electromyography (EMG) signals recorded through intramuscular electrodes (iEMG). A previous iEMG study has shown that in humans, the elbow extensors have higher ∆F than the elbow flexors. In this study, EMG signals were collected from the ankle extensors and flexors using high-density surface array electrodes during isometric sitting and standing at 10% - 30% maximum voluntary contraction. The signals were then decomposed into individual motor unit firings. We hypothesized that comparable to the upper limb, the lower limb extensor muscles (soleus) would have higher ∆F than the lower limb flexor muscles (tibialis anterior, TA). Contrary to our expectations, ∆F was higher in the TA than the soleus during sitting and standing despite the difference in cohort of participants and body positions. The TA also had significantly higher maximum discharge rate than the soleus while there was no difference in rate increase. When only the unit pairs with similar maximum discharge rates were compared, ∆F was still higher in the TA than the soleus. Future studies will focus on investigating the functional significance of the findings.