W. A. R. P.: A Radical Solution to Teaching Foundations

Molecular and Physicochemical Aspects of Local Anesthetics Acting on Nicotinic Acetylcholine Receptor-containing Membranes

“…Today, it is known that the inhibitory action of LAs on nerve conduction is primarily due to the interaction of the drug with voltage-gated Na + channels. Relevant aspects of the structure and function of voltagegated Na + channels on the nervous system can be found in several excellent reviews [1,2]. Additional experimental evidence supports the conjecture that LAs may also act on several ion channels (e.g., K + and Ca 2+ channels), ion pumps, enzymes, and neurotransmitter-gated ion channel receptors (reviewed in [3]).…”

Sensor Devices Inspired by the Five Senses: A Review

“…These GPCRsc an be founda ll across the animal kingdom and are commonly coupled to an intracellular trimeric guanine nucleotideb inding-protein (G-protein). Gproteins function as on/offs witches and consist of three subunits: a,b and g [34,35,37].U pon binding of as timulant to the GPCRanumber of its cytosolic segments undergo conformational changes enabling them to interact with the a-subunit of the G-protein. The a-subunit (G a ) acts as ag uanine-exchange factor( GEF) and mediates the activation and deactivation process.C onversion from the inactivet ot he active state is the result of guanosine diphosphate (GDP) releasef rom G a .N ext guanosinet riphosphate (GTP) rapidly binds to G a replacing GDP.T he GDP to GTPe xchange is facilitated by the high concentration of the GTP in the intracellular environment and its high binding affinity [35].…”

“…Ther esulting freeG a -GTP complexi se ssential for many transduction reactions as it interacts with effectors to instigate the next step in the transductionp athway.E ffectors in aG CPR pathways function eithera sm embrane bound ion-channels or as catalytic enzymes involved in the formationo fs econdary messenger molecules [35]. Commonly the b and g subunits remain bound together (G bg )i nac omplex and have been known to also interact with some effectors,s ometimes triggeringp arallel transduction pathways [35,37,39,40].A fter several minutes the G a -GTP complex is hydrolysed to aG a -GDPc omplex by the internal GTPase activity of the G a subunit [35,37]. TheG TPase activity is further managed and catalysedb y GTPase-activating proteins and regulators of G-protein signalling [ 37,39].T he G a -GDPc omplext hen reunites with aG bg complext hereby ceasing activation of the effector and terminating the transduction reaction [36].…”

“…Downstream from the effectors, the pathwayo ften leads to increase in low-molecular weight intracellular signallingm olecules whicho peratea ss econdary messengers,r egulating certain nucleotideg ated ion-channels and triggering protein kinases.A so utlined in the introduction, ion channel opening is key to generatinga ction potentials,c onverting chemicali nformationi nto electrical signals that the brain can interpret as sensations.T he role of protein kinases is to phosphorylate other specific proteins in the cell, mediating ad irectc ell response or in some cases facilitating negative-feedback regulatory loops by desensitizingG PCRs [40].O ne of the most important and common secondary messengersi sc yclic adenosine monophosphate (cAMP). Somee ffectors up-regulate cAMP and others down-regulate it, with varying results for membrane polarization depending on the specific pathway [36,37,39].O ther common secondary messengers are diacylglycerol (DAG), 1,4,5-inositol trisphosphate (IP 3 )a nd cyclic guanosine monophosphate (cGMP).…”

“…As econdary messenger is dispatched or an effect is realized( ion channel regulation) 5. In time the signallingp athway is desensitized throughf eedback regulation G-proteins can be dividedi nf our generalg roupsb ased on a-subunit effect, G s whiche licit as timulating effect on cAMP secondary messengerm olecules,t he G i/o family which evokes an inhibitory effect on cAMP,t he G q/11 family which commonly activates phospholipase C( PLC) in its downstream cascade,a nd the G 12/13 family which activate an N + /H + exchanger pathway as wella sp hospholipase A( PLA) and c-JunN H 2 -terminal kinase [36,37,39,41].T able 1g ives an overview of the G-proteins,e ffectors and secondary messengerm olecules involved in visual, olfactory and gustatorys ensation as well as the remaining G-protein classes.F or am ore extensive synopsis of knowne ffectors and G-proteinsw er efer to ad etailed review by Catterall et al [37].T he downstream pathways of each of the five senses will be discussed in more detail in an umbero fthe following paragraphs.…”