Second messengers, ion channels and pharmacology of airway smooth muscle

Abstract

Second messengers, ion channels and pharmacology of airway smooth muscle I.P. HallSecond messengers, ion channels and pharmacology of airway smooth muscle. I.P. Hall. #ERS Journals Ltd 2000. ABSTRACT: The airway smooth muscle cell is the chief effector cell governing the control of airway calibre in the human lung. The contractile state of the airway smooth muscle cell is predominantly influenced by the balance of constrictor and relaxant stimuli. Agents such as histamine and acetylcholine cause airway smooth muscle cells to contract through activation of specific cell surface receptors and engagement of signal transduction pathways and/or ion channels. The predominant pathway mediating constriction is activation of phospholipase C, with release of inositol 1,4,5-triphosphate and elevation of intracellular calcium levels.Relaxation is brought about predominantly by stimulation of adenylyl cyclase-coupled receptors (e.g. the b 2 -adrenoceptor) resulting in elevation of cell cyclic adenosine monophosphate content. Complex crosstalk occurs between both of these pathways and also ion channels expressed on the airway smooth muscle cell membrane, leading to careful regulation of airway smooth muscle tone.A greater understanding of the mechanisms governing control of these pathways will lead to the identification of novel therapeutic targets which will in turn lead to new agents for the treatment of asthma.

Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells

“…Hyvelin et al (22) reported that only ryr3 mRNA was expressed in human bronchial smooth muscle cells. The function of the type 3 ryanodine receptor is still poorly understood, whereas type 1 and type 2 ryanodine receptors have been clearly implicated in excitationcontraction coupling in skeletal and cardiac muscle (18). In the present study, caffeine, which depletes the SR via ryanodine activation and prevents it from refilling (52), had a small effect on the initial phase of increased [Ca 2ϩ ] i but a large effect on the sustained phase in all three types of HASM NKR-transfected cells.…”

“…However, a limitation of the interpretation of the results of the present study is that SKF-96365 also has a minor inhibitory effect on voltage-gated Ca 2ϩ channels (56). The sustained Ca 2ϩ response is important for maintaining the contractile response to agonist (18) and requires the continued presence of agonist (11,39). In the sustained phase, SOCE has been considered as the predominant source of Ca 2ϩ influx (11,35).…”

Regulation of store-operated Ca2+entry by CD38 in human airway smooth muscle

“…

(11,15,20,26,38,39,46) or by plasma membrane Ca 2ϩ influx.TNF␣, a potent proinflammatory cytokine found in bronchoalveolar lavage fluid (12) and sputum (50) from asthmatics, has been implicated as a mediator in the pathophysiology of asthma (45, 51, 52) and chronic obstructive pulmonary disease (8, 16). Indeed, TNF␣ has been shown to enhance ASM contractility (13,43,47 (11,20,46) as well as via ryanodine receptor (RyR) channels (15, 26), the latter resulting from increased levels of the novel second messenger cyclic ADP ribose (cADPR) (27,39).

…”

“…Indeed, TNF␣ has been shown to enhance ASM contractility (13,43,47 (11,20,46) as well as via ryanodine receptor (RyR) channels (15, 26), the latter resulting from increased levels of the novel second messenger cyclic ADP ribose (cADPR) (27,39). cADPR, in turn, is synthesized and degraded by the bifunctional ectoenzyme CD38 via ADP ribosyl cyclase and cADPR hydrolase activities, respectively (22).…”

“…Increased [Ca 2ϩ ] i in response to agonist stimulation (e.g., ACh, histamine) can occur via Ca 2ϩ release from sarcoplasmic reticulum (SR) (11,15,20,26,38,39,46) or by plasma membrane Ca 2ϩ influx.…”