Characterization of postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle

Weiser, Martin; Mutschler, E.; Lambrecht, Günter

doi:10.1007/pl00005104

Cited by 9 publications

(5 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, the rat anococcygeus responds to muscaric agonists. Muscarinic receptors of the M 3 subtype are present on smooth muscle where they induce contraction (Weiser et al, 1997). The current findings show acetylcholine-induced contraction of the anococcygeus muscle in a concentrationdependent fashion.…”

Section: Discussionmentioning

confidence: 86%

Antispasmodic and relaxant effects of the hidroalcoholic extract of Pimpinella anisum (Apiaceae) on rat anococcygeus smooth muscle

Tirapelli

Andrade

Cassano

et al. 2007

Journal of Ethnopharmacology

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 86%

Antispasmodic and relaxant effects of the hidroalcoholic extract of Pimpinella anisum (Apiaceae) on rat anococcygeus smooth muscle

Tirapelli

Andrade

Cassano

et al. 2007

Journal of Ethnopharmacology

View full text Add to dashboard Cite

“…1, A and B, haditoxin showed high similarity (80 -83%) with muscarinic toxin homologs (MTLP and MTLP-3) as well as similarity with muscarinic toxins (MT-␣, MT7, and MT3) (51-52%). As such, we examined the effects of haditoxin on in vitro smooth muscle preparations, the rat ileum and rat anococcygeus muscle, pharmacologically characterized to represent M2 (45) and M3 mAChRs (46), respectively. In both preparations, the protein had no effect on the contractile response of the muscle to exogenously applied ACh or electrical field stimulation, suggesting that haditoxin does not interact with M2 and M3 mAChRs (supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

Structural and Functional Characterization of a Novel Homodimeric Three-finger Neurotoxin from the Venom of Ophiophagus hannah (King Cobra)

Roy

Zhou

Chong

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Snake venoms are a mixture of pharmacologically active proteins and polypeptides that have led to the development of molecular probes and therapeutic agents. Here, we describe the structural and functional characterization of a novel neurotoxin, haditoxin, from the venom of Ophiophagus hannah (King cobra). Haditoxin exhibited novel pharmacology with antagonism toward muscle (␣␤␥␦) and neuronal (␣ 7 , ␣ 3 ␤ 2 , and ␣ 4 ␤ 2 ) nicotinic acetylcholine receptors (nAChRs) with highest affinity for ␣ 7 -nAChRs. The high resolution (1.5 Å ) crystal structure revealed haditoxin to be a homodimer, like -neurotoxins, which target neuronal ␣ 3 ␤ 2 -and ␣ 4 ␤ 2 -nAChRs. Interestingly however, the monomeric subunits of haditoxin were composed of a three-finger protein fold typical of curaremimetic shortchain ␣-neurotoxins. Biochemical studies confirmed that it existed as a non-covalent dimer species in solution. Its structural similarity to short-chain ␣-neurotoxins and -neurotoxins notwithstanding, haditoxin exhibited unique blockade of ␣ 7 -nAChRs (IC 50 180 nM), which is recognized by neither shortchain ␣-neurotoxins nor -neurotoxins. This is the first report of a dimeric short-chain ␣-neurotoxin interacting with neuronal ␣ 7 -nAChRs as well as the first homodimeric three-finger toxin to interact with muscle nAChRs.Snake venoms are a rich source of pharmacologically active proteins and polypeptides targeting a variety of receptors with high affinity and specificity (1). Because of their high specificity, some of these molecules have contributed significantly (a) to the isolation and characterization of different receptors and their subtypes in the field of molecular pharmacology and (b) as lead compounds in the development of therapeutic agents (2, 3). For example, the discovery of ␣-bungarotoxin, a postsynaptic neurotoxin from the venom of Bungarus multicinctus, led to the identification of the nicotinic acetylcholine receptor (nAChR), 3 the first isolated receptor protein (4) as well as the first one to be characterized electrophysiologically (5) and biochemically (6, 7). Subsequently, it was also used to characterize several other nAChRs (8 -10).Snake venom proteins can be broadly classified as enzymatic and non-enzymatic proteins. Three-finger toxins (3FTxs) are the largest group of non-enzymatic snake venom proteins (1, 11). They are most commonly found in the venoms of elapid and hydrophiid snakes. Recently, our laboratory has also demonstrated the presence of 3FTxs from colubrid venoms (12, 13), and 3FTx transcripts have been found in the venom gland transcriptome of viperid snakes (14, 15). The proteins in this family of toxins share a common structural scaffold of three ␤-sheeted loops emerging from a central core (11,16). Despite the overall similarity in structure, these proteins have diverse functional properties. Members of this family include neurotoxins targeting the cholinergic system (7, 11, 16), cytotoxins/cardiotoxins interacting with the cell membranes (17), calciseptine and related toxins that block th...

show abstract

“…Furthermore, wherever Schild analysis has been performed the plots for these antagonists have slopes of unity indicating that the M3 receptor is the only muscarinic subtype involved in mediating contractile responses to muscarinic agonists in vitro. Thus, direct smooth muscle contraction is mediated via the M3 receptor subtype in the cat oesophagus (Preiksaitis and Laurier, 1998), rat stomach (Lin et al, 1997), guinea pig and dog ileum (Honda et al, 1993;Shi and Sarna, 1997), guinea pig common bile duct (Karahan et al, 1991), guinea pig colon (Ehlert, 1999), guinea pig taenia caeci (Shen and Mitchelson, 1998) and rat anoccocygeus muscle (Weiser et al, 1997). Similarly, in the lower urinary tract, responses of the bladder have been shown to be mediated via M3 receptors in all species so far examined (for review see Chess- Williams, 2002) including the human bladder (Chess- Fetscher et al, 2002).…”

Section: Receptor Subtypes Mediating Direct Contractionmentioning

confidence: 99%

Muscarinic receptor subtypes of the bladder and gastrointestinal tract

Uchiyama

Chess-Williams

2004

J. Smooth Muscle Res.

105

View full text Add to dashboard Cite

The parasympathetic nervous system is responsible for maintaining normal intestinal and bladder function, contracting the smooth muscle by releasing the neurotransmitters acetylcholine (ACh) and ATP and relaxing sphincters by releasing nitric oxide. ACh is the main transmitter released and smooth muscle contraction is mediated via a mixed M2/M3 receptor population; M3 receptors acting via phospholipase C and M2 receptors acting via inhibition of adenylate cyclase. In ileal, colonic, gastric and bladder (detrusor) smooth muscle the density of M2 receptors is far greater than the density of M3 receptors, the M2:M3 ratio being 3:1 in most species including man. Despite the predominance of M2-receptors, direct contraction of intestinal and detrusor smooth muscle is mediated via the M3-receptor subtype and only this subtype is involved in contraction in vitro. Furthermore, knocking out the M3-receptor gene can have severe consequences on intestinal and bladder responses. In some tissues however M2-receptors may mediate an indirect "re-contraction" whereby a reduction in adenylate cyclase activity reverses the relaxation induced by beta-adrenoceptor stimulation. Thus, intestinal and bladder responses to muscarinic agonists are slightly depressed in M2 receptor knockout mice. The role of receptor subtypes in disease is unclear, but an enhancement of M2 receptor mediated responses has been reported to occur in diabetes. Animal models suggest that M2 receptors may play a greater role in some situations such as in the denervated bladder and intestine. In human disease the mechanisms operating are not so clear. Detrusor sensitivity to muscarinic agonists is enhanced in the neurogenic overactive bladder, but there is controversy surrounding the role of M2 receptors and conflicting results have been reported. Thus, the main muscarinic receptor mediating contraction in normal smooth muscle is the M3 receptor, but M2 receptors are also present and possibly may have an enhanced role in disease.

show abstract

Characterization of postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle

Cited by 9 publications

References 40 publications

Antispasmodic and relaxant effects of the hidroalcoholic extract of Pimpinella anisum (Apiaceae) on rat anococcygeus smooth muscle

Antispasmodic and relaxant effects of the hidroalcoholic extract of Pimpinella anisum (Apiaceae) on rat anococcygeus smooth muscle

Structural and Functional Characterization of a Novel Homodimeric Three-finger Neurotoxin from the Venom of Ophiophagus hannah (King Cobra)

Muscarinic receptor subtypes of the bladder and gastrointestinal tract

Contact Info

Product

Resources

About