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Abstract

Recently, genomics and proteomics have been utilized as advanced tools for investigation of cellular signalingpathways and molecular interactions, and elucidated promiscuous networks composed of numerous interactions amongpathways. However, some of these interactions are considered to be simply contributing to background ‘noise’ and othersare as ‘crosstalk’ biologically-relevant to cellular physiology, leading to synergy effects more than additive responses inan entire organism. Effort is now required to determine which interactions truly contribute to final physiological output. Areceptor is the prime example of connectors among the networks. It functions, not simply as a signaling gateway, but alsoas an active trader by forming inter-receptor dimers. Furthermore, various receptors can modulate the function of the otherreceptors by input to common intracellular signaling pathways, establishing functional crosstalk among networks. Ourfindings by combined analyses of gene polymorphisms of two separate genes present evidences that such is the case withhuman body in a clinical setting: 1) an integrated effect of epidermal growth factor receptor (EGFR) and protease activatedreceptor-1 (PAR-1) on susceptibility to airway hyperresponsiveness (AHR), and 2) a crosstalk effect between muscarinicacetylcholine receptor (mAChRs) and β2 adrenoceptor (β2AR) on bronchodilatory response to anticholinergicagents in patients with COPD. These results indicate that these interactions are unlikely to be ‘noise’ but functionallyrelevant‘crosstalk’ in a human body. This review attempts to highlight the clinically-relevant ‘crosstalk’ paradigm in ahuman body which provides us a novel insight necessary to investigate pathophysiology in common multifactorial diseasesand to develop new drugs.

Keywords:Clinical relevance, signaling crosstalk, receptor dimer formation, integrated effects of multiple receptors, systemsbiology, pathophysiology, multifactorial diseases, bronchial asthma, chronic obstructive pulmonary disease (COPD), drug discovery

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