Title:Cellular Signaling Crosstalk Between Multiple Receptors for Investigation of Pathophysiology in Multifactorial Diseases - What is Clinically-Relevant Crosstalk?
Volume: 20
Issue: 9
Author(s): T. Yoshikawa and H. Kanazawa
Affiliation:
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
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.
