Endothelin-1 activates ETA receptors to increase intracellular calcium in model sensory neurons

Abstract

Endothelin-1 (ET-1) induces endothelin-A (ETA) receptor-mediated pain and selective excitation of nociceptors. Here we studied ET-1-induced changes in intracellular calcium (Ca2+in) in Fura-2 loaded mouse neuroblastoma-rat dorsal root ganglion hybrid cells (ND7/104). ET-1 (1-400 nM) induced concentration-dependent, transient increases in Ca2+in, probably of intracellular source. Responses to repeated application declined with increasing ET-1 concentration, implying receptor desensitization. Treatment of cells with the selective ETA receptor antagonist, BQ-123, produced a dose-dependent inhibition of the response that was 20% of ET-1 alone (IC50 = 20 nM, KI = 7 nM). No inhibition of the calcium response was observed with the selective ETB antagonist, BQ-788 (10-1000 nM). These results demonstrate that ET-1 induces dose- and ETA receptor-dependent release of Ca2+in in nociceptor-like neurons, and permit further examination of the pathways that underlie ET-1-induced pain signaling.

ET-1 induces cortical spreading depression via activation of the ETAreceptor/phospholipase C pathway in vivo

“…In addition, ET-1 induced a transient calcium release via Ins(1,4,5)P 3 from the sarcoplasmic reticulum and a sustained release related to receptor-operated calcium-permeable channels of the plasma membrane in rabbit cortical arterioles (22). Similar transient intracellular calcium increases, dependent on the endoplasmic reticulum, and sustained increases, dependent on extracellular calcium, were also induced by ET-1 in neurons (34,67).…”

“…We confirmed that the ET B receptor was not involved because the ET B receptor agonist BQ-3020 did not induce CSDs. Whereas the ET A receptor mediating CSD makes a primary astroglial target of ET-1 unlikely, it is known that ET-1 can release intracellular calcium via that receptor subtype in both VSM and certain neurons, suggesting a link between ET A receptor activation and PLC in VSM and neurons (22,67).…”

“…Interestingly, these effects of ET-1 on astrocytes are only inhibited significantly if both ET A and ET B receptors are simultaneously blocked (3). This is in contrast to several ET-1 effects on the vasculature or neurons that are inhibited by the application of either ET A or ET B receptor antagonists (48,59,66,67). In a complex system such as the brain in vivo, it may be difficult to decide which cellular targets/functions mediate the complex effect of ET-1 on the neuronal/astroglial network.…”

Urotensin‐II regulates intracellular calcium in dissociated rat spinal cord neurons

“…Receptor desensitization is an important cellular mechanism preventing cell over-stimulation (Filipeanu et al 2001) and is a common phenomenon for many peptide receptors including endothelin (Zhou et al 2001) and angiotensin II (Filipeanu et al 2001). In this regard, the U-II effects showed a marked desensitization in rat vasculature (Camarda et al 2002).…”

Animal Models of Cancer Pain

“…For instance, the peptide endothelin 1, which is expressed by numerous tumor types, is release by fibrosarcoma cells and contributes to bone cancer pain. 6,34,86,179,193 High levels of endothelin 1 were found and activation of primary afferent fibers occurred in mice with calcaneous fibrosarcoma tumor but not in control mice implanted with nonpainful melanoma cells into the calcaneous bone. 179 The finding that hyperalgesia occurred only in fibrosarcoma-implanted mice and not in melanoma-implanted mice suggests that endothelin 1 contributes to cancer-related pain associated with fibrosarcoma tumors.…”