Receptor clefts

The deduced preselection of the dipolar species in the electric field of the receptor may be assumed to enormously accelerate the diffusional approach of dipolar ligands [153]. The resulting formation of a diffusional encounter complex Figure 4.8) represents the initial step in molecular recognition and selection which is followed by a sequence of consecutive steps, during which more and more substructures make contact with the subsites of the receptor cleft, which eventually may fully encompass an inhibitor molecule when being complementary. 

In addition, researchers can survey the surface and clefts of a macromolecule for potential receptor sites based on Hgand distance ranges "use the common distance range of the superimposed atoms" (116) to faciHtate the development of a "pharmacophore" or critical contact assembly besides the Hgand... 

Most effective differentiation of the receptor between substrates will occur when multiple interactions are involved in the recognition process. The more binding regions (contact area) present, the stronger and more selective will be the recognition (17). This is the case for receptor molecules that contain intramolecular cavities, clefts or pockets into which the substrate may fit (Fig. 1). 

However, all the receptors hitherto discussed are monomolecular species which possess a monomolecular cavity, pocket, cleft, groove or combination of it including the recognition sites to yield a molecular receptor—substrate complex. They can be assembled and preserved ia solution although there are dependences (see below). By way of contrast, molecular recognition demonstrated ia the foUowiag comes from multimolecular assembly and organization of a nonsolution phase such as polymer materials and crystals. 

Mice homozygous for an ETA receptor gene disruption show craniofacial malformations, such as cleft palate, micrognathia, microtia and microglossia. ETA (—/—) mice die shortly after birth due to respiratory failure. Mice with an ET-l-null mutation show the same cranciofacial malformations and, in addition, cardiovascular disorders (e.g. septal defects, abnormal cardial outflow tract, aortic arch and subclavian arteries). 

Various lines of evidence indicate that ACh binds to the M1-M5 receptors within a cleft enclosed by the ring-like arrangement of TM I-VII, about 10-15 A away from the membrane surface [1, 3]. ACh binding induces as yet poorly understood changes in the arrangement of individual transmembrane helices. These conformational changes are then transmitted to the intracellular... 

Non-selective Cation Channels. Figure 1 The nicotinic acetylcholine receptor (nAChR) is localized within the cell membrane above the cell membrane is the synaptic cleft, below the cytoplasm. Drawing of the closed (left) and open (right) nAChR showing acetylcholine (ACh) binding and cation movement. Dimensions of the receptor were taken from references [2, 3]. 

Psychostimulants. Figure 2 Dopamine molecules have two different possible targets. Both ways are initially increased by DAT inhibition caused by methylphenidate pre- and postsynaptic dopamine receptors. Stimulation of postsynaptic receptors results in inhibition of presynaptic action potential generation. On the other hand, presynaptic receptor stimulation leads to a transmission inhibition of action potentials. Therefore, both mechanisms are responsible for a decrease in vesicular depletion of dopamine into the synaptic cleft (adapted from [2]). 

Class IIHLA molecules are expressed on the surface of antigen-presenting cells. They play a key role in presentation of processed linear peptide antigens of at least nine amino acids to T cells. Antigen is bound to the HLA antigen binding cleft formed by the a and 3 chains of the HLA class II molecule. This tri-molecular HLA-antigen complex binds in turn to the variable portion of the T-cell receptor. 

Atropine acts as an antagonist of acetylcholine at muscarinic receptors, but not at nicotinic receptors. By acting as an antagonist, it can prevent overstimulation of muscarinic receptors by the excessive quantities of acetylcholine remaining in the synaptic cleft when AChE is inhibited. The dose of atropine needs to be carefully controlled because it is toxic. 

Acetylcholinesterase is a component of the postsynaptic membrane of cholinergic synapses of the nervous system in both vertebrates and invertebrates. Its structure and function has been described in Chapter 10, Section 10.2.4. Its essential role in the postsynaptic membrane is hydrolysis of the neurotransmitter acetylcholine in order to terminate the stimulation of nicotinic and muscarinic receptors (Figure 16.2). Thus, inhibitors of the enzyme cause a buildup of acetylcholine in the synaptic cleft and consequent overstimulation of the receptors, leading to depolarization of the postsynaptic membrane and synaptic block. 

Figure 3.1 Schematic representation of a generic excitatory synapse in the brain. The presynaptic terminal releases the transmitter glutamate by fusion of transmitter vesicles with the nerve terminal membrane. Glutamate diffuses rapidly across the synaptic cleft to bind to and activate AMPA and NMDA receptors. In addition, glutamate may bind to metabotropic G-protein-coupled glutamate receptors located perisynaptically to cause initiation of intracellular signalling via the G-protein, Gq, to activate the enzyme phospholipase and hence produce inositol triphosphate (IP3) which can release Ca from intracellular calcium stores...

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