Cellular Signaling Crosstalk Between Multiple Receptors for Investigation of Pathophysiology in Multifactorial Diseases - What is Clinically-Relevant Crosstalk?

T.      Yoshikawa; H.      Kanazawa

Abstract

Recently, genomics and proteomics have been utilized as advanced tools for investigation of cellular signaling pathways and molecular interactions, and elucidated promiscuous networks composed of numerous interactions among pathways. However, some of these interactions are considered to be simply contributing to background ‘noise’ and others are as ‘crosstalk’ biologically-relevant to cellular physiology, leading to synergy effects more than additive responses in an entire organism. Effort is now required to determine which interactions truly contribute to final physiological output. A receptor is the prime example of connectors among the networks. It functions, not simply as a signaling gateway, but also as an active trader by forming inter-receptor dimers. Furthermore, various receptors can modulate the function of the other receptors by input to common intracellular signaling pathways, establishing functional crosstalk among networks. Our findings by combined analyses of gene polymorphisms of two separate genes present evidences that such is the case with human body in a clinical setting: 1) an integrated effect of epidermal growth factor receptor (EGFR) and protease activated receptor-1 (PAR-1) on susceptibility to airway hyperresponsiveness (AHR), and 2) a crosstalk effect between muscarinic acetylcholine receptor (mAChRs) and β2 adrenoceptor (β2AR) on bronchodilatory response to anticholinergic agents 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 a human body which provides us a novel insight necessary to investigate pathophysiology in common multifactorial diseases and to develop new drugs.

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