Receptors with intrinsic ion channels

Some of the most revealing studies of partial agonism (including Stephenson s seminal work) have been done with tissues in which G-proteins (see Chapters 2 and 7) provide the link between receptor activation and initiation of the response. In contrast to the situation with fast receptors with intrinsic ion channels (see above), it is not yet possible to observe the activity of individual G-protein-coupled receptors (with the potential exception of some that are linked to potassium channels) however, enough is known to show that the mechanisms are complex. The interpretation of differences in efficacy for agonists acting at such receptors is correspondingly less certain. 

Fig. 5.2. Structural principles of transmembrane receptors, a) Representation of the most important functional domains of transmembrane receptors, b) Examples of subunit structures. Transmembrane receptors can exist in a monomeric form (1), dimeric form (2) and as higher oligomers (3,4). Further subunits may associate at the extracellular and cytosohc domains, via disulfide bridges (3) or via non-covalent interactions (4). c) Examples of structures of the transmembrane domains of receptors. The transmembrane domain may be composed of an a-hehx (1) or several a-helices linked by loops at the cytosolic and extracellular side (2). The 7-helix transmembrane receptors are a frequently occurring receptor type (see 5.3). Several subunits of a transmembrane protein may associate into an ohgomeric structure (3), as is the case for voltage-controUed ion channels (e.g., K channel) or for receptors with intrinsic ion channel function (see Chapter 17).

Neurotransmitter-controlled Receptors with Intrinsic Ion Channel Function... 

At least two classes of neurotransmitter-controlled receptors with intrinsic ion channel function can be differentiated. One class includes receptors with the specific ligands acetylcholine, y-aminobutyric acid (GABA), glycine and serotonin. 

C. Potassium channels NON-SELECTIVE CATION CHANNELS AS DRUG TARGETS DIRECT LIGANDGATED ION CHANNELS (RECEPTORS WITH INTRINSIC ION CHANNEL)... 

Note that one endogenous mediator may activate several GPCRs 13 for serotonin 9 for adrenaline and noradrenaline 8 for glutamate 5 for dopamine 5 for acetylcholine 4 for histamine 2 for GABA. Also, some mediators activate GPCRs but also receptors with intrinsic ion channel. 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

Ligand-gated ion channels G protein-coupled receptors Receptors with intrinsic enzyme activity INTRODUCTION... 

As a result of coupling considerations and structural information derived from cloning and expression studies, the P2 purinoceptors are now divided into two main classes. These are (1) the metabotropic P2Y receptors, which are G-protein-coupled, and (2) the ionotropic P2X receptors, which are intrinsic ion channel receptors. [It should be noted that details of nomenclature for these receptor have changed several times recently, particularly with regard to use of subscripts. The version adopted here, is that currently recommended by the NC-IUPHAR Nomenclature Subcommittee for Purinoceptors.]... 

FIGURE 4.5 Gated ion channel receptors, receptors with intrinsic enzymatic activity and receptors associated with cytosohc tyrosine kinases. 

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