Receptors, head

The affinity of MLA for the nicotinic receptor in the cockroach nerve cord also appeared to be rather less than that for the housefly head receptor, suggesting that there might be different subclasses of insect receptor. This theory was proposed recently by Battersby and Hall (13), who showed that lobeline, another plant-derived cholinergic ligand, had a higher affinity for the cockroach receptor than for the housefly head receptor. 

The interest in vesicles as models for cell biomembranes has led to much work on the interactions within and between lipid layers. The primary contributions to vesicle stability and curvature include those familiar to us already, the electrostatic interactions between charged head groups (Chapter V) and the van der Waals interaction between layers (Chapter VI). An additional force due to thermal fluctuations in membranes produces a steric repulsion between membranes known as the Helfrich or undulation interaction. This force has been quantified by Sackmann and co-workers using reflection interference contrast microscopy to monitor vesicles weakly adhering to a solid substrate [78]. Membrane fluctuation forces may influence the interactions between proteins embedded in them [79]. Finally, in balance with these forces, bending elasticity helps determine shape transitions [80], interactions between inclusions [81], aggregation of membrane junctions [82], and unbinding of pinched membranes [83]. Specific interactions between membrane embedded receptors add an additional complication to biomembrane behavior. These have been stud-... 

Figure S.21 The hemaggiutinin moiecuie is formed from three subunits. Each of these subunits Is anchored In the membrane of the influenza vims. The globular heads contain the receptor sites that bind to sialic acid residues on the surface of eukaryotic cells. A major part of the subunit interface is formed by the three long intertwining helices, one from each subunit. (Adapted from I. Wilson et al.. Nature 289 366-373, 1981.)...

Figure 5.23 The globular head of the hemagglutinin subunit Is a distorted jelly roll stmcture (a). P strand 1 contains a long Insertion, and P strand 8 contains a bulge in the corresponding position. Each of these two strands is therefore subdivided Into shorter P strands. The loop region between P strands 3 and 4 contains a short a helix, which forms one side of the receptor binding site (yellow circle). A schematic diagram (b) Illustrates the organization of the p strands into a jelly roll motif.

The individual domains of the two receptors both have structures similar to that of the glucocorticoid receptor, and they bind to DNA in a similar way, with their recognition helices in the major groove. The dimer contacts are, however, totally different. In the glucocorticoid receptor, which binds to a palindromic DNA sequence like the 434 repressor described in Chapter 8, the domains interact symmetrically in a head-to-head fashion equivalent... 

Schreiber R, Brocco M, Audinot V, et al (l-(2,5-Dimethoxy-4 iodophenyl)-2-amino-propane)-induced head-twitches in the rat are mediated by 5-hydroxytryptamine (5-HT) 2A receptors modulation by novel 5-HT2A/2C antagonists, Dj antagonists and 5-HTagonists. J Pharmacol Exp Ther 273 101—112, 1995 Screaton GR, Singer M, Cairns HS, et al Hyperpyrexia and rhabdomyolysis after MDMA ( ecstasy ) abuse. Lancet 399 667—668, 1992... 

Joseph K, Ghebrehiwet B. Peerschke El. Reid KB. Kaplan AP Identification of the zinc-dependent endothelial cell binding protein for high molecular weight kininogen and factor Xll identity with the receptor that binds to the globular heads of Clq (gClq-R). Proc Natl Acad Sci USA 1996 93 8552-8557. 

A series of palmitoylethanolamine-derived inhibitors has been described in the literature as FAAH inhibitors [77, 78]. This study explored the effect of shortening the chain length and replacement of the ethanolamine head group with primary, secondary and tertiary amide alternatives. Of the compounds synthesised and tested, two compounds gave reasonable affinities for FAAH inhibition, palmitoyl-isopropylamide (63) (IC50 = 13/rM) and palmitoyl-allylamide (64) (IC50 = 3.4/rM). Both these compounds had little affinity for either CBi or CB2 receptors. 

Replacement of the ethanolamine head group is also well tolerated. Substitution with a cyclopropyl (243) [37], allyl (244) or propargyl group (245) [164] all led to an increase in binding affinity compared to AEA. Replacement of the head group with aromatics is also allowed. The phenyl derivative (246) retains affinity at the CBi receptor [37], whereas the 2-substituted A-methyl pyrrole (247) has a 2-fold improved affinity compared to AEA [167]. Interestingly, the 3-substituted furan derivative (23) that has micromolar affinity for the AEA transporter (see above) does not bind to the CBi receptor, but has good affinity for the CB2 receptor [167]. These results are summarised in Table 6.20. 

The intracellular processes which precede membrane activation appear to differ from those of MOE neurones, in that cyclic nucleotide gating may not occur. The transduction process which induces current flow in snake VN neurones, utilises as a putative second-messenger the modulator compound inositol triphosphate — Ins. (1,4,5) P3 = IP3 (Liu et al, 1999 Taniguichi et al, 2000). The proposed channel component associated with the microvillous membrane is one of the transient receptor potential family (TRPC-2 Heading Fig., pp. 94), the p-splice... 

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