Estrogenic Modulation of Ionic Channels, Pumps and Exchangers in Airway Smooth Muscle

Abstract

To preserve ionic homeostasis (primarily Ca²⁺, K⁺, Na⁺, and Cl^-), in the airway smooth muscle (ASM) numerous transporters (channels, exchangers, and pumps) regulate the influx and efflux of these ions. Many of intracellular processes depend on continuous ionic permeation, including exocytosis, contraction, metabolism, transcription, fecundation, proliferation, and apoptosis. These mechanisms are precisely regulated, for instance, through hormonal activity. The lipophilic nature of steroidal hormones allows their free transit into the cell where, in most cases, they occupy their cognate receptor to generate genomic actions. In the sense, estrogens can stimulate development, proliferation, migration, and survival of target cells, including in lung physiology. Non-genomic actions on the other hand do not imply estrogen's intracellular receptor occupation, nor do they initiate transcription and are mostly immediate to the stimulus. Among estrogen's non genomic responses regulation of calcium homeostasis and contraction and relaxation processes play paramount roles in ASM. On the other hand, disruption of calcium homeostasis has been closely associated with some ASM pathological mechanism. Thus, this paper intends to summarize the effects of estrogen on ionic handling proteins in ASM. The considerable diversity, range and power of estrogens regulates ionic homeostasis through genomic and non-genomic mechanisms.

Keywords: airway smooth muscle; channels; estrogen; exchangers; pumps; receptors.

Figure 1

Ion transport proteins. Ion transport proteins are classified into three groups: channels, exchangers, and pumps. These three types of proteins maintain the homeostasis of the intracellular ions either through facilitated or active transport, and changes in the ionic intracellular concentrations can initiate cellular processes. In blue, a chlorine channel is represented; in red, a non-selective cation channel; in purple, the Na⁺/Ca²⁺ exchanger; and in green, the plasma membrane Ca²⁺ ATPase. EC, extracellular; Cl⁻, chloride, Na⁺, sodium; Ca²⁺, calcium; ATP, adenosine triphosphate.

Figure 2

Estrogen biosynthesis and sites of action. The main site of estrogen synthesis are the ovaries. However, several extragonadal synthesis sites exist, and the main requirement for local estrogen production is the tissue expression of the aromatase enzyme. Once the estrogen is synthesized, it can have local activity or it can be liberated into the blood stream, where it will be carried to its action site bound to the sex hormone binding globulin or to albumin. When the estrogen reaches its target, it can produce its effect through three modes of action: through the activation of the estrogen receptors ERα and ERβ, or by interacting with its membrane receptor GPR30 or directly with its target protein. GPR30, G protein-coupled receptor 30.

Figure 3

Calcium handling mechanisms in airway smooth muscle and their modulation by estrogens. E2 through non-genomic effects inhibits SOCCs, and the chronic exposure to an ERβ-specific agonist decreases the expression of STIM1 and Orai1, and an ERα-specific agonist increases the expression of STIM1 and Orai1.The genomic effect of E2 increases the expression of CD38, although the non-genomic effect is still unknown. E2 acutely inhibits the LVDCC and the chronic exposure, via ERβ pathway, inhibits this channel. In the sarcoplasmic reticulum, the chronic exposure with an ERβ-specific agonist inhibits the increase in SERCA expression caused by exposure to TNF-α and IL-13. The genomic and non-genomic effects of E2 over RyR2, IP₃R1, NCX and PMCA are still not reported. EC, extracellular; Ac, Acute; Ch, Chronic; IP₃, inositol 1,4,5-trisphosphate; [Ca²⁺]i, intracellular calcium concentration; [Ca²⁺]e, extracellular calcium concentration; [Ca²⁺]SR, sarcoplasmic reticulum calcium concentration; E2_, 17β estradiol; ERα, estrogen receptor α; ERβ, estrogen receptor β; L-VDCC, L-type voltage dependent Ca²⁺ channel; SOCC, store-operated Ca²⁺ channel, NCX, Na⁺/Ca²⁺ Exchanger; PMCA, plasma membrane Ca²⁺ ATPase; IP₃R, inositol 1,4,5-trisphosphate receptor; RyR, Ryanodine receptor; SERCA, sarcoplasmic reticulum Ca²⁺ ATPase; FKBP-12.6, 12.6 kDa FK506-binding protein; Orai1; STIM1, stromal interacting molecule; SARAF, Store-operated Ca²⁺ entry-associated regulatory factor.

Figure 4

Potassium, sodium and chloride handling mechanisms in airway smooth muscle and their modulation by estrogens. Estrogen acutely increases the BK_Ca activity through the NO/GC/cGMP/PKG pathway phosphorylation of the β subunit, and when the SNP C818T is expressed, E2 compensates for the reduced activation of the channel through the activation of the NO/GC/cGMP/PKG pathway. The activity of E2 over the Kv, NKA, NKCC, Nav, CFTR, CACCs, and GABA_A receptor proteins in the ASM is still unknown. EC, extracellular; E2, estradiol; Ac, Acute; SR, sarcoplasmic reticulum; Cl⁻, chloride, K⁺, potassium; Na⁺, sodium; Ca²⁺, calcium; P, phosphate; BK_Ca, high-conductance Ca²⁺-activated K⁺ channel; Kv, voltage-activated potassium channels; NKA, Na⁺/K⁺ ATPase; NKCC, Na⁺/K⁺/Cl⁻ cotransporter; Nav, voltage-gated Na⁺ channels; CACCs, Ca²⁺-activated Cl⁻ channels; CFTR, cystic fibrosis transmembrane conductance regulator; GABA, gamma amino butyric acid; GABA_A, activated chloride channel; RyR2, ryanodine receptor 2; IP₃R, inositol 1,4,5-trisphosphate receptor; NO, nitric oxide; GC, guanyl cyclase; cGMP, cyclic guanosine monophosphate; PKG, protein kinase G; GTP, guanosine triphosphate; GDP, guanosine diphosphate.