Involvement of Ca2+ signaling in tachykinin-mediated contractile responses in swine trachea

Abstract

Neuropeptide tachykinins, present within sensory nerves, have been implicated as neurotransmitters involved in nonadrenergic and noncholinergic airway muscle contraction. The signal transduction pathways of tachykinins on muscle contraction and Ca2+ mobilization were investigated in swine trachea. Tachykinins, substance P (SP) and neurokinin A (NKA), concentration (1 nM to 1 microM)-dependently induced contractile responses with removal of epithelium, whereas neurokinin B (NKB) did not alter the muscle tension. The SP- and NKA-evoked muscle contractions were inhibited by NK1-R antagonist L732138, but not by either NK2-R antagonist MDL29913 or NK3-R antagonist SB218795. Consistently, SP-elicited increase in [Ca2+]i was abolished by NK1-R antagonist, neither by NK2-R nor NK3-R antagonists. The SP-induced muscular responses were significantly inhibited by L-type Ca2+ channel blocker verapamil and withdrawal of external Ca2+. Caffeine (10 mM) or ryanodine (50 microM) also partly suppressed the SP-induced muscle responses. Inhibition of inositol 1,4,5-trisphosphate (InsP3) receptor with 2-APB (75 microM) potently attenuated SP-evoked Ca2+ mobilization and muscle contraction, which was further inhibited by 2-APB under Ca2+-free external solution, but not completely. Unexpectedly, simultaneous blockade of InsP3 receptor and ryanodine receptor (RyR) by 2-APB and ryanodine enhanced SP-evoked muscle contraction and Ca2+ mobilization. This potentiation was virtually abolished by removal of external Ca2+, suggesting native Ca2+ channels may contribute to this phenomenon. These results demonstrate that tachykinins produce a potent muscle contraction associated with Ca2+ mobilization via tachykinin NK1- R-dependent activation of multiple signal transduction pathways involving Ca2+ influx and release of Ca2+ from InsP3- and ryanodine-sensitive Ca2+ stores. Blockade of both InsP3 receptor and RyR enhances the Ca2+ influx through native Ca2+ channels in plasma membrane, which is crucial to Ca2+ signaling in response to NK1 receptor activation.

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

“…In the present study, NKRselective agonist-induced [Ca 2ϩ ] i increases were partially blocked by verapamil. Likewise, Lin et al (28) reported that substance P-evoked airway smooth muscle contraction and transient Ca 2ϩ mobilization were partially inhibited by verapamil, indicating that the NKR-mediated [Ca 2ϩ ] i increases are associated with activation of voltage-gated Ca 2ϩ channels. They further demonstrated that smooth muscle contraction and [Ca 2ϩ ] i increases activated by substance P were also partially blocked under Ca 2ϩ -free external conditions (28).…”

“…Likewise, Lin et al (28) reported that substance P-evoked airway smooth muscle contraction and transient Ca 2ϩ mobilization were partially inhibited by verapamil, indicating that the NKR-mediated [Ca 2ϩ ] i increases are associated with activation of voltage-gated Ca 2ϩ channels. They further demonstrated that smooth muscle contraction and [Ca 2ϩ ] i increases activated by substance P were also partially blocked under Ca 2ϩ -free external conditions (28). Together, these findings indicate that Ca 2ϩ influx from the extracellular space is a component of the transient initial phase of NKR-mediated transient [Ca 2ϩ ] i increases.…”

Broad-spectrum antiemetic efficacy of the l-type calcium channel blocker amlodipine in the least shrew (Cryptotis parva)

“…Activation of 5-HT 3 -receptor (5-HT 3 R) is known to increase cytoplasmic Ca 2+ levels via extracellular influx through L-type-and 5-HT 3 R Ca 2+ -permeable channels (Hargreaves et al, 1996;Homma et al, 2006;Ronde and Nichols, 1997;Takenouchi and Munekata, 1998). Additional evidence indicate that Ca 2+ influx is also linked to activation of other emetogenic receptors including SP tachykinin NK 1 (Lallemend et al, 2003;Lin et al, 2005;Miyano et al, 2010;Suzuki et al, 2010), dopamine D 2 (Aman et al, 2007;Wu et al, 2006), cholinergic M 1 (Oliveir and Correia-de-Sa, 2005;Sculptoreano et al, 2001), and histaminergic H 1 (Barajas et al, 2008) receptors. Moreover, other emetogens such as prostaglandins (Almirza et al, 2012;Rodríguez-Lagunas et al, 2010), cisplatin (Günes et al, 2009;Splettstoesser et al, 2007), rotavirus NSP4 protein (Hagbom et al, 2012;Hyser et al, 2010) and bacterial toxins (Poppoff and Poulain, 2010;Timar Peregrin et al, 1999) have the ability to induce extracellular Ca 2+ influx through Ca 2+ channels present in the cell membrane.…”

Role of Calcium in Vomiting

“…NK 1 R stimulation by substance P or corresponding selective agonists such as GR73632, can increase cytosolic Ca 2+ concentration. In fact GR73632-induced activation of NK 1 Rs can evoke intracellular Ca 2+ release from the sarco/ endoplasmic reticulum stores via Gα/q-mediated phospholipase C pathway, which subsequently evokes extracellular Ca 2+ influx through L-type Ca 2+ channels (LTCCs) [17][18][19]. The serotonergic 5-HT 3 receptor (5-HT 3 R) is a Ca 2+ -permeable ligand-gated ion channel [20].…”