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Review
. 2009 Oct;22(5):388-97.
doi: 10.1016/j.pupt.2008.09.006. Epub 2008 Oct 19.

Ion channel regulation of intracellular calcium and airway smooth muscle function

Jose F Perez-Zoghbi  1 , Charlotta Karner, Satoru Ito, Malcolm Shepherd, Yazan Alrashdan, Michael J Sanderson
Affiliations
Free PMC article
Review

Ion channel regulation of intracellular calcium and airway smooth muscle function

Jose F Perez-Zoghbi et al. Pulm Pharmacol Ther. 2009 Oct.
Free PMC article

Abstract

Airway hyper-responsiveness associated with asthma is mediated by airway smooth muscle cells (SMCs) and has a complicated etiology involving increases in cell contraction and proliferation and the secretion of inflammatory mediators. Although these pathological changes are diverse, a common feature associated with their regulation is a change in intracellular Ca(2+) concentration ([Ca(2+)](i)). Because the [Ca(2+)](i) itself is a function of the activity and expression of a variety of ion channels, in both the plasma membrane and sarcoplasmic reticulum of the SMC, the modification of this ion channel activity may predispose airway SMCs to hyper-responsiveness. Our objective is to review how ion channels determine the [Ca(2+)](i) and influence the function of airway SMCs and emphasize the potential of ion channels as sites for therapeutic approaches to asthma.

Figures

Figure 1
Figure 1. Ion channels and their contribution to Ca2+ changes in airway smooth muscle cells
The binding of agonist to its receptor activates phospholipase C (PLC) via membrane G-proteins to synthesize inositol trisphosphate (IP3) and diacylglycerol (DAG) from membrane lipids. IP3 (blue triangles) diffuses throughout the cell and binds to the IP3R, sensitizing it to Ca2+, which stimulates the opening of the receptor to allow the release of Ca2+ from the sarcoplasmic reticulum (SR). The released Ca2+ in turn stimulates (+ black arrow) Ca2+-induced Ca2+ release from adjacent, sensitized IP3Rs which results in the propagation of a Ca2+ wave. The released Ca2+ subsequently inactivates the IP3R (− red arrow) and the Ca2+ is re- accumulated in the SR via Ca2+ pumps (SERCA). The repetitive release and uptake of Ca2+ results in Ca2+ oscillations. DAG and its derivatives (e.g. arachidonic acid, AA) move in the membrane to activate receptor-operated Ca2+ influx or channels (ROC) to replenish internal Ca2+ stores. During the Ca2+ oscillations, the Ca2+ store is partially depleted and this is sensed by STIM1 in the SR. STIM1 translocates through the SR membrane to aggregate with and activate store-operated Ca2+ entry or channels (SOC) (consisting of Orai1 or TRP proteins) to replenish the internal Ca2+ store. Ryanodine receptors (RyR) may release internal Ca2+ in the form of Ca2+ sparks to activate near by KCa channels to induce membrane hyperpolarization. KCa1.1 channels may be replaced with KCa3.1 channels during cell proliferation to alter membrane voltage which may influence voltage-dependent Ca2+ channels (VDC). Stretch-activated channels (SA) are directly gated by physical stimuli.
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