Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction

Abstract

Bitter taste receptors (TAS2Rs) of the tongue likely evolved to evoke signals for avoiding ingestion of plant toxins. We found expression of TAS2Rs on human airway smooth muscle (ASM) and considered these to be avoidance receptors for inhalants, leading to ASM contraction and bronchospasm. TAS2R agonists such as saccharin, chloroquine and denatonium evoked increased ASM [Ca2+]i in a Gβγ, PLCβ and IP3-receptor dependent manner which would be expected (like acetylcholine) to evoke contraction. Paradoxically, bitter tastants caused relaxation of isolated ASM, and dilation of airways that was 3-fold greater than β-agonists. Relaxation by TAS2Rs is from a localized [Ca2+]i response at the cell membrane which opens BKCa channels leading to ASM membrane hyperpolarization. Inhaled bitter tastants decreased airway obstruction in an asthma mouse model. Given the need for efficacious bronchodilators for treating obstructive lung diseases, this pathway can be exploited for therapy with the thousands of known synthetic and naturally occurring bitter tastants.

Calcineurin upregulates local Ca2+signaling through ryanodine receptor-1 in airway smooth muscle cells

“…STICs have been shown to be involved in ASMC contraction (16) and asthmatic AHR (48). In human ASMCs, some believe the spark-STOC relationship underlies relaxation of ASMCs following activation of bitter taste receptors (10). Nevertheless, previous reports have shown that ASMC contraction is not significantly affected by LTCC blockers in isolated animal ASMCs and tissues, and clinical studies indicate that LTCC blockers are ineffective in the treatment of airway smooth muscle contraction and asthma (9, 14, 38).…”

“…Ca 2ϩ sparks have been observed in equine (44), guinea pig (51), porcine (32), mouse (26), and human ASMCs (10). These local Ca 2ϩ events are known to regulate ASMC membrane potential through the activation of hyperpolarizing spontaneous transient outward currents (STOCs) or depolarizing spontaneous transient inward currents (STICs) (49).…”

“…Oppositely, Ca 2ϩ sparks activate STICs due to a close association of RyRs with highly dense clusters of Ca 2ϩ -activated Cl Ϫ (Ca Cl ) channels (1) that have now been identified as the transmembrane protein 16A Ca Cl channel (5,36,46). Of great clinical importance in determining the cause of asthmatic AHR, Ca 2ϩ sparks have recently been shown to exist in human ASMCs (10) and to be upregulated in freshly isolated ASMCs from a sensitized murine model of asthma (41). Thus, Ca 2ϩ sparks may play an important role in physiological and pathological functions in ASMCs.…”

Olfaction in the kidney: ‘smelling’ gut microbial metabolites

“…2009; Deshpande et al . 2010). Olfactory receptors play roles in the migration of muscle cells (Griffin et al .…”

A “bitter” end to asthma revealed

“…Maybe the problem with those old remedies is that they are not bitter enough. Jokes aside, there may actually be some truth in this, as shown by a recent study from Stephen B. Liggett's laboratory in the University of Maryland (Deshpande et al, 2010). In a survey for G-protein coupled receptors (GPCR) in human airway smooth muscle (ASM), this group inadvertently identified several types of bitter taste receptors, which are members of the GPCR family.…”