Over the last few decades, there has been an explosion of scientific publications reporting the many and varied roles of transient receptor potential (TRP) ion channels in physiological and pathological systems throughout the body. The aim of this review is to summarize the existing literature on the role of TRP channels in the lungs and discuss what is known about their function under normal and diseased conditions. The review will focus mainly on the pathogenesis and symptoms of asthma and chronic obstructive pulmonary disease and the role of four members of the TRP family: TRPA1, TRPV1, TRPV4 and TRPM8. We hope that the article will help the reader understand the role of TRP channels in the normal airway and how their function may be changed in the context of respiratory disease. LINKED ARTICLESThis article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10 Abbreviation 4αPDD, 4α-phorbol-12,13-didecanoate; AHR, airway hyper-responsiveness; CGRP, calcitonin gene-related peptide; COPD, chronic obstructive pulmonary disease; DRG, dorsal root ganglia; HASM, human airway smooth muscle; LAR, late asthmatic response: OTC, over-the-counter; PAR, protease-activated receptors; SNP, single nucleotide polymorphism; TRP, transient receptor potential Introduction to transient receptor potential (TRP) ion channelsTRP channels were discovered in the eye of the Drosophila melanogaster fly, and named for their transient response to bright light (Montell and Rubin, 1989). Several homologues have since been identified that have a well conserved 'TRP domain' consisting of 23-25 amino acids. There are 28 mammalian TRP subunits, categorized in to six related protein subfamilies, based on sequence homology (Clapham, 2003). TRP ion channels are widely expressed throughout the body, and can respond to a remarkable diversity of intracellular and extracellular stimuli. This capacity to be activated by seemingly disparate mechanisms has led to the perception of TRP channels as multiple signal integrators. The TRP channel superfamily comprises a group of cation-selective proteins, which display a general preference for calcium ions. TRPs exhibit six transmembrane-spanning domains with the channel pore located between transmembrane domains 5 and 6, intracellular C and N termini, and varying degrees of ankyrin repeats (Caterina et al., 1997;Ramsey et al., 2006). Current evidence suggests that active TRP channels are formed by four subunits, and could assemble as homo-or hetero-tetramers (Latorre et al., 2009). For more in-depth information on TRP channels, we suggest consulting some of the excellent reviews including Clapham, 2003;Nilius et al. 2005;Bessac & Jordt, 2008;Preti et al. 2012. Aim of the reviewThe aim of this review is to describe the TRP channels, which have been explored in more depth regarding their role in physiological and pathological mechanisms in the airways (TRPA1, TRPV1, TRPV4 and TRPM8; receptor nomenclature ...

The nuclear hormone receptor gene superfamily encodes structurally related proteins that regulate transcription of target genes. These macromolecules include receptors for steroid and thyroid hormones, vitamins, and other proteins for which no ligands have been found. These receptors have modular domains. The DNA-binding domain directs the receptors to bind specific DNA sequences as monomers, homodimers, or heterodimers. The ligand-binding domain responds to binding of the cognate hormone; this domain and the amino terminal domain interact with other transcription factors. Nuclear receptor-specific actions are derived from a combination of diverse elements, including availability of ligand, receptors, and nonreceptor factors; target-site structure; interactions with other proteins, such as the general transcription factors; and influences of other signaling pathways. These interactions result in ligand-regulated and ligand-independent effects on initiation of transcription of the target genes. Understanding the mechanisms of nuclear receptor action will enhance our knowledge of transcription and hormone influences on disease and facilitate the design of drugs with greater therapeutic value.

The circadian clock regulates many aspects of immunity. Bacterial infections are affected by time of day, but the mechanisms involved remain undefined. Here we show that loss of the core clock protein BMAL1 in macrophages confers protection against pneumococcal pneumonia. Infected mice show both reduced weight loss and lower bacterial burden in circulating blood. In vivo studies of macrophage phagocytosis reveal increased bacterial ingestion following Bmal1 deletion, which was also seen in vitro. BMAL1−/− macrophages exhibited marked differences in actin cytoskeletal organization, a phosphoproteome enriched for cytoskeletal changes, with reduced phosphocofilin and increased active RhoA. Further analysis of the BMAL1−/− macrophages identified altered cell morphology and increased motility. Mechanistically, BMAL1 regulated a network of cell movement genes, 148 of which were within 100 kb of high-confidence BMAL1 binding sites. Links to RhoA function were identified, with 29 genes impacting RhoA expression or activation. RhoA inhibition restored the phagocytic phenotype to that seen in control macrophages. In summary, we identify a surprising gain of antibacterial function due to loss of BMAL1 in macrophages, associated with a RhoA-dependent cytoskeletal change, an increase in cell motility, and gain of phagocytic function.