Interaction with membranes

The pain appears to arise from the formation of melittin pores in the membranes of nociceptors, free nerve endings that detect harmful ( noxious —thus the name) stimuli of violent mechanical stress, high temperatures, and irritant chemicals. The creation of pores by melittin depends on the nociceptor membrane potential. Melittin in water solution is tetrameric. However, melittin interacting with membranes in the absence of a membrane potential is monomeric and shows no evidence of oligomer... 

FIGURE 5.3 Different types of functional readouts of agonism. Receptors need not mediate cellular response but may demonstrate behaviors such as internalization into the cytoplasm of the cell (mechanism 1). Receptors can also interact with membrane proteins such as G-proteins (mechanism 2) and produce cytosolic messenger molecules (mechanism 3), which can go on to mediate gene expression (mechanism 4). Receptors can also mediate changes in cellular metabolism (mechanism 5). 

It has been generally accepted that anesthetics interact with membrane lipids as a primary step of anesthesia. The detailed mechanism of the anesthetic action is, however, still controversial. This is mainly due to the absence of specific information on delivery sites in membranes. The NMR data for the delivery site of drugs in membranes are of great use. 

Before the first indication of the existence of cannabinoid receptors, the prevailing theory on the mechanism of cannabinoid activity was that cannabinoids exert their effects by nonspecific interactions with cell membrane lipids (Makriyannis, 1990). Such interactions can increase the membrane fluidity, perturb the lipid bilayer and concomitantly alter the function of membrane-associated proteins (Loh, 1980). A plethora of experimental evidence suggests that cannabinoids interact with membrane lipids and modify the properties of membranes. However, the relevance of these phenomena to biological activities is still only, at best, correlative. An important conundrum associated with the membrane theories of cannabinoid activity is uncertainty over whether cannabinoids can achieve in vivo membrane concentrations comparable to the relatively high concentrations used in in vitro biophysical studies (Makriyannis, 1995). It may be possible that local high concentrations are attainable under certain physiological circumstances, and, if so, some of the cannabinoid activities may indeed be mediated through membrane perturbation. 

Recently, numerous studies reported the application of homonuclear and heteronuclear selective recoupling schemes on uniformly labelled ligand interacting with membrane receptors. The polarization exchange curves were fitted with the two-spin model and showed that it is possible to determine intemuclear distances up to 4.5 A.118... 

Flewelling, R. F., Hubbell, W. L., Hydrophobic ion interactions with membranes. Thermodynamic analysis of tetraphenylphosphonium binding to vesicles, Biophys. J. 1986, 49, 531— 540. 

In neurons and non-neuronal cells, kinesin is associated with a variety of MBOs, ranging from synaptic vesicles to mitochondria to lysosomes. In addition to its role in fast axonal transport and related phenomena in non-neuronal cells, kinesin appears to be involved in constitutive cycling of membranes between the Golgi and endoplasmic reticulum. However, kinesin is not associated with all cellular membranes. For example, the nucleus, membranes of the Golgi complex and the plasma membrane all appear to lack kinesin. Kinesin interactions with membranes are thought to involve the light chains and carboxyl termini of heavy chains. However, neither this selectivity nor the molecular basis for binding of kinesin and other motors to membranes is well understood. 

Thus, lipoproteins could be injected over the surface of a lipid covered SPR sensor in a detergent free buffer solution and showed spontaneous insertion into the artificial membrane.171 Again two hydro-phobic modifications are necessary for stable insertion into the lipid layer, whereas lipoproteins with a farnesyl group only dissociate significantly faster out of the membrane. Therefore the isoprenylation of a protein is sufficient to allow interaction with membraneous structures, while trapping of the molecule at a particular location requires a second hydrophobic anchor. Interaction between the Ras protein and its effector Raf-kinase depends on complex formation of Ras with GTP (instead of the Ras GDP complex, present in the resting cell). If a synthetically modified Ras protein with a palmi-... 

The same relationships between free metal ions and total metal concentrations hold as above. Equation (4) may include the concentration of hydrophobic ligands. However, the occurrence of hydrophobic complexes is particularly relevant to the interactions with membranes. 

One inherent property of peptides that interact with membranes is that self-association or even aggregation will interfere with solubilization by organic solvents or micelles. The preparation, purification and sample preparation of extremely hydrophobic (often transmembrane) peptides is nontrivial and has been addressed by only a few papers [74—79]. 

Fullerene showed antibacterial activity, which can be attributed to different interactions of C60 with biomolecules (Da Ros et al., 1996). In fact, there is a possibility to induce cell membrane disruption. The fullerene sphere seems not really adaptable to planar cellular surface, but for sure the hydrophobic surface can easily interact with membrane lipids and intercalate into them. However, it has been demonstrated that fullerene derivatives can inhibit bacterial growth by unpairing the respiratory chain. There is, first, a decrease of oxygen uptake at low fullerene derivative concentration, and then an increase of oxygen uptake, which is followed by an enhancement of hydrogen peroxide production. The higher concentration of C60 seems to produce an electron leak from the bacterial respiratory chain (Mashino et al., 2003). 

Membranes separate cells from their external environment, and the internal components of cells from each other. Many biochemical processes taking place within cells occur on a framework of membranes. Toxicant interactions with membranes figure prominently in many types of toxic effect. 

The receptors start a second messenger cascade that is initiated by activation of G-proteins in the cell. These, in turn, interact with membrane-bound adenylyl cyclase, which catalyzes the formation of cyclic adenine monophosphate (cAMP) and opening of cAMP-gated cation channels. Depolarization then brings about an action potential, which travels along the axon of the olfactory sensory neuron. Many of the molecular components of this cascade are olfactoiy specific. 

PDA vesicles have been used to screen small molecules that are known to interact with membranes. Screening of almost 40 compounds against PDA/DMPC liposomes... 

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