3.5

• G protein coupled signalling


  Increases the diversity of response outcomes at the target tissue through slower and longer-lasting processes

  
• Two major G protein coupled signalling pathways

  • Phospholipase C-b (PLC-b)
  • Adenylyl cyclase (Adenylate cyclase)

  
• PLC and AC pathways

  Often converge on a common effect to increase intracellular Ca++, which can then affect a range of cellular activities either in itself or through the protein, Ca++-Calmodulin

  
• Autonomic Nervous System (ANS)


  Organization into a two-neuron chain with an interposed ganglion between pre- and post-ganglionic neurons that differ in terms of type of synapses they form, neurotransmitter agents they use and type of receptor these agents act on

  
• Muscarinic ACh receptors


  Parasympathetic post-ganglionic transmission involves these receptors
• Adrenergic NA receptors


  Sympathetic post-ganglionic transmission involves these receptors

  
• β adrenergic NA receptor

  Can produce opposing outcomes, and how the two ANS divisions can act to oppose each other
• Two major types of receptors at which the Endocrine system can act

  • Membrane-bound receptors
  • Intracellular receptors

  
• Non-steroid hormones


  Can act via either one of the two major pathways of Adenylyl cyclase (to produce cAMP as the 2nd messenger) or PLCb (to produce Ca++ as the 2nd messenger)
• Steroid (and thyroid) hormones

  Can have genomic and non-genomic effects, and where are located the receptors for each of these signalling pathways
• Steroid hormone receptors have special binding sites for the hormone and separate binding sites for DNA
• Steroid hormone receptors need to be escorted (chaperoned) to the nucleus after binding the hormone, to bind to the DNA, but that this interaction with the DNA is "noisy" in that the same pathways can be activated by different hormones

  
• Terminating the action of GPRCs by desensitization

  1. Homologous desensitization - activated GPCR is downregulated

  2. Heterologous desensitization - activated GPCR causes downregulation of a different GPCR

  3. Phosphorylation of cytoplasmic part of GPCR by protein kinases (PKA, GRKs)

  4. Arrestin molecules bind to phosphorylated GPCR, preventing GPCR from binding G protein and marking GPCR for internalization

  
• Desensitization process


  • Cue pathway activates G protein-coupled receptor kinases (GRKs) that phosphorylate GPCR
  • Arrestin binds to phosphorylated GPCR, finalising desensitization and marking receptor for internalization
  • Reduction in receptor numbers reduces efficiency of neurotransmission

  
• Autonomic Nervous System (ANS)


  Part of Nervous System that controls internal structures

  
• Internal structures controlled by ANS

  • Smooth muscle (walls of viscera and blood vessels)
  • Adipose tissue
  • Some eye muscles
  • Anal sphincter
  • Genitals
  • Kidney & ureter
  • Adrenal medulla
  • Glands (lacrimal, nasal, salivary, sweat, apocrine)
  • Piloerector muscles (skin hairs)
  • Spleen
• ANS divisions


  • Sympathetic Nervous System
  • Parasympathetic Nervous System
  • Enteric Nervous System (found only within digestive system)

  
• Traditional view of ANS

  • Motor system consisting of motor neurons controlling body structures other than skeletal muscle

  
• Current view of ANS

  • Has motor and sensory components
  • Motor components are efferent arm carrying information from CNS to body structures
  • Sensory components are afferent arm carrying information to CNS from body structures receiving ANS motor input

  
• ANS motor arm


  Two-neuron chain from CNS to target tissue

  
• ANS motor arm vs Somatic Nervous System

  ANS has two-neuron chain from CNS to target tissue, Somatic Nervous System has one-neuron chain from CNS to skeletal muscle

  
• Differences between pre-ganglionic and post-ganglionic ANS neurons

  • Pre-ganglionic neurons are faster conducting than post-ganglionic neurons
  • Post-ganglionic neurons have smaller axon diameters and are unmyelinated, ensuring slower conduction velocities
• Transmission at the ganglion

  • Fast and relatively simple, obeys rules of neuron-to-neuron signalling
  • Uses acetylcholine (ACh) acting on nicotinic AChRs for fast post-synaptic responses

  
• Post-ganglionic transmission


  • Highly branched axons with multiple varicosities allowing action on many cells in target tissue
  • Can involve diffuse transmission
  • Generally uses G protein coupled receptors (GPCRs) which can produce fast, slow, and long-term effects

  
• Transmitters used in ANS divisions

  • Pre-ganglionic: ACh

  Sympathetic post-ganglionic: Noradrenaline

  Parasympathetic post-ganglionic: ACh
• All ANS transmitters act on G protein coupled receptors (GPCRs)

  
• Post-ganglionic transmitter in Sympathetic division

  Noradrenaline (Norepineprhine)
• All transmitters act on G protein coupled receptors (GPCRs)

  
• GPCRs allow for great diversity of responses
• Other chemicals involved in ANS signalling


  • Neuropeptides (NPY, CGRP, VIP, Somatostatin, DYN, CCK, GRP, ENK, Galanin)
  • Purines (ATP)
  • Other chemicals
• Transmitters and neuromodulators


  They act as transmitters or as neuromodulators
• Different patterns and rates of action potentials in the neuron alter the combinations of chemicals released
• Different combinations of transmitters and neuromodulators released alter the end-effects at the tissues and organs
• Muscarinic ACh receptors (mAChRs)

  GPCRs that ACh acts on in Parasympathetic division
• Nicotinic ACh receptors (nAChRs)

  Ionotropic receptors that ACh acts on in pre-ganglionic transmission
• Activation of mAChRs


  1. Binding of ACh allows inactive G protein to exchange GDP for GTP and activate

  2. Activated G protein components move to activate or inhibit Adenylate cyclase

  3. Adenylate cyclase breaks down ATP to produce cAMP

  4. cAMP activates protein kinase to trigger cellular responses

  
• Activation of mAChRs via PLC pathway

  1. Activated G protein activates Phospholipase C

  2. PLC activates Phosphatidylinositol to form PIP2

  3. PIP2 activates Diacylglycerol and Inositol triphosphate

  4. Diacylglycerol activates Protein kinase C

  5. Inositol triphosphate causes release of Ca++ as 3rd messenger

  
• Alpha-adrenergic receptors (a-NARs)


  GPCRs that noradrenaline acts on in Sympathetic division

  
• Beta-adrenergic receptors (b-NARs)


  GPCRs that noradrenaline acts on in Sympathetic division

  
• Activation of a1-NAR


  1. Coupled to Gs protein

  2. Exerts effects through PLC pathway

  3. Increases intracellular Ca++ and activates Protein Kinase C