Protease-activated receptor-2 inhibits BK channel activity in bronchopulmonary sensory neurons

Moss, Charles R.; Gilbert, Carolyn A.; Gabriel, Sabry A.; Gu, Qihai

doi:10.1016/j.neulet.2015.01.020

Cited by 6 publications

(3 citation statements)

References 26 publications

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“…However, to what extent ADAM10 protease could affect function of this channel remains to be elucidated. Moreover, as mentioned in above section, rapid modulation of N-type voltage-gated Ca 2+ channels and BK channel function occurs following PAR-2 activation in sensory or peripheral nerves in vitro (Kim et al, 2014 ; Moss et al, 2015 ). Interestingly, MMPs 2/9 were shown to directly alter the gating properties and function of retinal cyclic nucleotide-gated channel in concentration-dependent manner by proteolysis of extracellular domain of the receptor (Meighan et al, 2012 , 2013 ).…”

Section: The Role Of Extracellular Proteolysis In Shaping Neuronal Exmentioning

confidence: 97%

“…However, most recently, PARs were also implicated in regulation of neuronal excitability through modulation of ion channels function and opposite conclusions were drawn. In bronchopulmonary sensory neurons, activation of PAR-2 for 2 min with activating peptide reduced large conductance Ca 2+ -activated potassium channel (BK) current, which resulted in increased excitability (Moss et al, 2015 ). Thus, it is plausible that activation of PAR-2 in various neurons results in different functional outcomes and therefore it remains to be further established in vivo whether PAR-2 has an anti-seizure and antiepileptogenic role (see also Figure 1 ).…”

Section: The Role Of Extracellular Proteolysis In Shaping Neuronal Exmentioning

confidence: 99%

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Diverse impact of acute and long-term extracellular proteolytic activity on plasticity of neuronal excitability

Wójtowicz

Brzdąk

Mozrzymas

2015

Front. Cell. Neurosci.

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Learning and memory require alteration in number and strength of existing synaptic connections. Extracellular proteolysis within the synapses has been shown to play a pivotal role in synaptic plasticity by determining synapse structure, function, and number. Although synaptic plasticity of excitatory synapses is generally acknowledged to play a crucial role in formation of memory traces, some components of neural plasticity are reflected by nonsynaptic changes. Since information in neural networks is ultimately conveyed with action potentials, scaling of neuronal excitability could significantly enhance or dampen the outcome of dendritic integration, boost neuronal information storage capacity and ultimately learning. However, the underlying mechanism is poorly understood. With this regard, several lines of evidence and our most recent study support a view that activity of extracellular proteases might affect information processing in neuronal networks by affecting targets beyond synapses. Here, we review the most recent studies addressing the impact of extracellular proteolysis on plasticity of neuronal excitability and discuss how enzymatic activity may alter input-output/transfer function of neurons, supporting cognitive processes. Interestingly, extracellular proteolysis may alter intrinsic neuronal excitability and excitation/inhibition balance both rapidly (time of minutes to hours) and in long-term window. Moreover, it appears that by cleavage of extracellular matrix (ECM) constituents, proteases may modulate function of ion channels or alter inhibitory drive and hence facilitate active participation of dendrites and axon initial segments (AISs) in adjusting neuronal input/output function. Altogether, a picture emerges whereby both rapid and long-term extracellular proteolysis may influence some aspects of information processing in neurons, such as initiation of action potential, spike frequency adaptation, properties of action potential and dendritic backpropagation.

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Section: The Role Of Extracellular Proteolysis In Shaping Neuronal Exmentioning

confidence: 97%

Section: The Role Of Extracellular Proteolysis In Shaping Neuronal Exmentioning

confidence: 99%

Diverse impact of acute and long-term extracellular proteolytic activity on plasticity of neuronal excitability

Wójtowicz

Brzdąk

Mozrzymas

2015

Front. Cell. Neurosci.

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“…Additional contributions from activation of PAR2 on other cells by endogenous proteases cannot be discounted. One study reported that PAR2 activation in isolated bronchopulmonary neurons inhibits K+ channel activity and increases sensory neuron excitability that might contribute to hyperresponsiveness (Moss et al, 2015). PAR2 activation can also have beneficial effects in the lung.…”

Section: Discussionmentioning

confidence: 99%

Proteinase‐activated receptor‐2 antagonist C391 inhibits Alternaria‐induced airway epithelial signalling and asthma indicators in acute exposure mouse models

Rivas

Yee

Addison

et al. 2022

British J Pharmacology

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Background and Purpose Despite the availability of a variety of treatment options, many asthma patients have poorly controlled disease with frequent exacerbations. Proteinase‐activated receptor‐2 (PAR2) has been identified in preclinical animal models as important to asthma initiation and progression following allergen exposure. Proteinase activation of PAR2 raises intracellular Ca2+, inducing MAPK and β‐arrestin signalling in the airway, leading to inflammatory and protective effects. We have developed C391, a potent PAR2 antagonist effective in blocking peptidomimetic‐ and trypsin‐induced PAR2 signalling in vitro as well as reducing inflammatory PAR2‐associated pain in vivo. We hypothesized that PAR2 antagonism by C391 would attenuate allergen‐induced acutely expressed asthma indicators in murine models. Experimental Approach We evaluated the ability of C391 to alter Alternaria alternata‐induced PAR2 signalling pathways in vitro using a human airway epithelial cell line that naturally expresses PAR2 (16HBE14o−) and a transfected embryonic cell line (HEK 293). We next evaluated the ability for C391 to reduce A. alternata‐induced acutely expressed asthma indicators in vivo in two murine strains. Key Results C391 blocked A. alternata‐induced, PAR2‐dependent Ca2+ and MAPK signalling in 16HBE14o− cells, as well as β‐arrestin recruitment in HEK 293 cells. C391 effectively attenuated A. alternata‐induced inflammation, mucus production, mucus cell hyperplasia and airway hyperresponsiveness in acute allergen‐challenged murine models. Conclusions and Implications To our best knowledge, this is the first demonstration of pharmacological intervention of PAR2 to reduce allergen‐induced asthma indicators in vivo. These data support further development of PAR2 antagonists as potential first‐in‐class allergic asthma drugs.

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Protease-activated receptors in health and disease

Peach

Edgington-Mitchell

Bunnett

et al. 2023

Physiological Reviews

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Although generally regarded as degradatory enzymes, certain proteases are also signaling molecules that specifically control cellular functions by cleaving protease-activated receptors (PARs). The four known PARs are members of the large family of G protein-coupled receptors. These transmembrane receptors control most physiological and pathological processes and are the target of a large proportion of therapeutic drugs. Signaling proteases include enzymes from the circulation, from immune, inflammatory epithelial and cancer cells, as well as from commensal and pathogenic bacteria. Advances in our understanding of the structure and function of PARs provide insights into how diverse proteases activate these receptors to regulate physiological and pathological processes in most tissues and organ systems. The realization that proteases and PARs are key mediators of disease, coupled with advances in understanding the atomic level structure of PARs and their mechanisms of signaling in subcellular microdomains, has spurred the development of antagonists, some of which have advanced to the clinic. Herein we review the discovery, structure and function of this receptor system, highlight the contribution of PARs to homeostatic control, and discuss the potential of PAR antagonists for the treatment of major diseases.

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Protease-activated receptor-2 inhibits BK channel activity in bronchopulmonary sensory neurons

Cited by 6 publications

References 26 publications

Diverse impact of acute and long-term extracellular proteolytic activity on plasticity of neuronal excitability

Diverse impact of acute and long-term extracellular proteolytic activity on plasticity of neuronal excitability

Proteinase‐activated receptor‐2 antagonist C391 inhibits Alternaria‐induced airway epithelial signalling and asthma indicators in acute exposure mouse models

Protease-activated receptors in health and disease

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