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Testosterone augments β2 adrenergic receptor genomic transcription increasing salbutamol relaxation in airway smooth muscle

Carbajal-García, Abril, Reyes-García, Jorge, Casas-Hernández, María F., Flores-Soto, Edgar, Díaz-Hernández, Verónica, Solís-Chagoyán, Héctor, Sommer, Bettina, Montaño, Luis M.
Molecular and cellular endocrinology 2020 v.510 pp. 110801
4-aminopyridine, Western blotting, actinomycin D, adolescents, androgen receptors, asthma, beta-2 adrenergic receptors, boys, calcium, chronic exposure, cycloheximide, fluorescent antibody technique, genomics, girls, guinea pigs, infancy, men, myocytes, potassium, potassium channels, protein synthesis inhibitors, puberty, serum albumin, smooth muscle, testosterone, transcription (genetics)
Androgens in asthmatic men may be linked to asthma severity, acting via nongenomic and genomic effects. This ailment affects boys more than girls during infancy, and this proportion reverses in puberty. Plasmatic androgen concentration in young men increases at this age and might be related to lower asthma symptoms. Nongenomic actions occur in a brief period and are independent of the androgen receptor (AR), while genomic effects depend on AR, take hours-days and are modified by transcription or protein synthesis inhibitors. Guinea pig tracheas chronic incubation with testosterone (TES, 40 nM, 48 h) potentiates salbutamol-induced relaxation, an effect that was reversed by flutamide, not observed when tissues were pre-incubated with TES-bovine serum albumin (TES-BSA) nor when tissues were preincubated with TES for 15–60 min. In tracheal myocytes, TES chronic incubation increases salbutamol-induced K⁺ currents (IK⁺), an effect that was also reversed by flutamide, actinomycin D and cycloheximide and not seen with TES-BSA. The increment in IK⁺ was blocked by 4-aminopyridine and iberiotoxin, indicating that delayed rectifier K⁺ and high-conductance Ca²⁺ activated K⁺ channels were involved in the TES potentiation effect. Immunofluorescence studies showed that chronic TES augmented the β₂ adrenergic receptor (β₂-AR) expression in ASM and this finding was corroborated by q-PCR and Western blot assays. β₂-AR affinity for salbutamol after TES incubation was increased. In conclusion, chronic exposure to physiological TES concentration of the guinea pig ASM promotes β₂-AR upregulation favoring β₂ adrenergic responses and probably limiting the severity of the asthmatic exacerbations in teenage boys and men.