Targeting calcium signaling by inositol trisphosphate receptors: A novel mechanism for the anti-asthmatic effects of Houttuynia cordata

Abstract

<p>Asthma is a chronic <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/inflammatory-disorder" title="Learn more about inflammatory disease from ScienceDirect's AI-generated Topic Pages">inflammatory disease</a> characterized by airway <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/hypersensitivity" title="Learn more about hypersensitivity from ScienceDirect's AI-generated Topic Pages">hypersensitivity</a> and remodeling. The current <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/therapeutic-procedure" title="Learn more about treatments from ScienceDirect's AI-generated Topic Pages">treatments</a> provide only short-term benefits and may have undesirable side effects; thus, alternative or supplementary therapy is needed. Because <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/intracellular-calcium" title="Learn more about intracellular calcium from ScienceDirect's AI-generated Topic Pages">intracellular calcium</a> (Ca²⁺) signaling plays an essential role in regulating the <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/muscle-contractility" title="Learn more about contractility from ScienceDirect's AI-generated Topic Pages">contractility</a> and remodeling of <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/airway-smooth-muscle-cell" title="Learn more about airway smooth muscle cells from ScienceDirect's AI-generated Topic Pages">airway smooth muscle cells</a>, the targeting of Ca²⁺ signaling is a potential therapeutic strategy for asthma. <em><a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/houttuynia-cordata" title="Learn more about Houttuynia cordata from ScienceDirect's AI-generated Topic Pages">Houttuynia cordata</a></em> is a traditional <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/chinese-herbs" title="Learn more about Chinese herb from ScienceDirect's AI-generated Topic Pages">Chinese herb</a> that is used to treat asthma due to its anti-allergic and anti-inflammatory properties. We hypothesized that <em>H. cordata</em> might modulate intracellular Ca²⁺ signaling and could help relieve asthmatic <a href="https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/airway-remodeling" title="Learn more about airway remodeling from ScienceDirect's AI-generated Topic Pages">airway remodeling</a>. We found that the mRNA and protein levels of <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/inositol-trisphosphate-receptor" title="Learn more about inositol trisphosphate receptors from ScienceDirect's AI-generated Topic Pages">inositol trisphosphate receptors</a> (IP₃Rs) were elevated in interleukin-stimulated primary human bronchial <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/smooth-muscle-cell" title="Learn more about smooth muscle cells from ScienceDirect's AI-generated Topic Pages">smooth muscle cells</a> and a house dust mite–sensitized model of asthma. The upregulation of IP₃R expression enhanced intracellular Ca²⁺ release upon stimulation and contributed to airway remodeling in asthma. Intriguingly, pretreatment with <em>H. cordata</em> essential oil rectified the disruption of Ca²⁺ signaling, mitigated asthma development, and prevented airway narrowing. Furthermore, our analysis suggested that houttuynin/2-undecanone could be the bioactive component in <em>H. cordata</em> essential oil because we found similar IP₃R suppression in response to the commercially available derivative sodium houttuyfonate. An <em><a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/in-silico" title="Learn more about in silico from ScienceDirect's AI-generated Topic Pages">in silico</a></em> analysis showed that houttuynin, which downregulates IP₃R expression, binds to the IP₃ binding domain of IP₃R and may mediate a direct inhibitory effect. In summary, our findings suggest that <em>H. cordata</em> is a potential alternative treatment choice that may reduce asthma severity by targeting the dysregulation of Ca²⁺ signaling.<br></p>