Increased Cholinergic Signaling

Overview

• Cholinergic signalling refers to the activation of receptors bound with acetylcholine. Receptors for acetylcholine are collectively referred to as either acetylcholine or cholinergic receptors. They break down into 2 different classes, muscarinic and nicotinic. Each receptor type is associated with specific downstream effects. The lists below are manifestations of associated with each receptor class.

  • Muscarinic: increased salivation, lacrimation, perspiration, miosis, blurred vision, abdominal cramps, vomiting, diarrhea, increased bronchial secretion, bronchoconstriction, urinary frequency, bradycardia, hypotension (Costa)

  • Nicotinic: tachycardia, transient hypertension, muscle fasciculations, twitching, cramps, generalized weakness, flaccid paralysis (Costa)

Signal Transduction

• The signal transmission mechanisms of both nicotinic and muscarinic cholinergic receptors has been intensively studied.

  • The nicotinic acetylcholine receptor (nAchR) is associated with triggering excitatory responses in motor neurons and skeletal muscle cells (Lodish, 2000). Overstimulation of the diaphragm via nicotinic receptors can lead to respiratory arrest (De Candole, 1953).

    • The nAchR has been extensively studied in neuromuscular junctions. It is a ligand-gated cation channel that allows passage of both potassium and sodium ions. Opening of nAchR ligand-gated ion channels produces a net depolarization at the muscle cell membrane, which leads to release of intracellular calcium, which triggers muscle contraction (Lodish, 2000). In this manner, acetylcholine accumulation can lead to paralysis via overstimulation of nicotinic receptors.  

  • Muscarinic receptors can transmit inhibitory signals. They are expressed on pre- and postsynaptic neurons, and on non-neuronal tissues throughout the body (Lodish, 2000).

  • Muscarinic receptors in the peripheral nervous system are activated by parasympathetic nerves present in airway smooth muscle, submucosal glands, and blood vessels where they trigger bronchoconstriction, mucus secretion, and vasodilatation, respectively (Coulson, 2003). 

    • All muscarinic receptors are G-protein coupled receptors, but the specific features depends on the subtype.

Neuromodulator Role

• In addition to breaking down acetylcholine’s effects in terms of the receptor types, researchers have started to look at acetylcholine’s effects in terms of acting as a neurotransmitter and as a neuromodulator. Classical neurotransmitters act on a time scale of one millisecond to tens of milliseconds. Some researchers have proposed that acetylcholine also acts as a neuromodulator that influences synaptic transmission, plasticity and coordinated firing of groups of neurons over time scales that are much longer than the millisecond time frames associated with neurotransmitters (Picciotto, 2012, Luchicchi, 2014).

• In humans

  • Pupils - human patients experiencing cholinergic poisoning constricted or pinpointed pupils are frequently reported in clinical cohort studies covering organophosphate exposure (Wadia, 1974, Peter, 2014). 

• In embryonic fish and frogs

  • Spontaneous movements in developing fish and frog embryos are defined as flexing or side-to-side motion of the trunk or tail and free-swimming activity, defined as bilateral rhythmic flexing of the tail. Embryos were observed under a dissection microscope and the number of movements per minute was recorded. Spontaneous motion is measured at 1 day post fertilization (dpf) in zebrafish embryos and at 2 dpf in Xenopus (Watson, 2014).

  • Embryonic swimming activity in fish and frogs was measured at 5 dpf by placing larvae-containing dishes above an 8-wedged pie chart grid and counting the number of times a larvae crossed a grid line during a 1-min interval (Watson, 2014).

• Costa.  Toxic effects of pesticides.  In Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. pp 1055-1106.

• De Candole, C.A., Douglas, W.W., Evans, C.L., Holmes, R., Spencer, K.E., Torrance, R.W., Wilson, K.M. 1953. The failure of respiration in death by anticholinesterase poisoning. Br J Pharmacol Chemother. 8(4):466-75.

• Picciotto MR, Higley MJ, Mineur YS., Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012 Oct 4;76(1):116-29.

• Luchicchi A, Bloem B, Viaña JN, Mansvelder HD, Role LW., Illuminating the role of cholinergic signaling in circuits of attention and emotionally salient behaviors. Front Synaptic Neurosci. 2014 Oct 27;6:24. doi: 10.3389/fnsyn.2014.00024. eCollection 2014.

• Wadia RS, Sadagopan C, Amin RB, Sardesai HV. Neurological manifestations of organophosphorous insecticide poisoning. J Neurol Neurosurg Psychiatry. 1974 Jul;37(7):841-7.

• Watson, Fiona L., Hayden Schmidt, Zackery K. Turman, Natalie Hole, Hena Garcia, Jonathan Gregg, Joseph Tilghman, and Erica A. Fradinger. 2014. “Organophosphate Pesticides Induce Morphological Abnormalities and Decrease Locomotor Activity and Heart Rate in Danio Rerio and Xenopus Laevis.” Environmental Toxicology and Chemistry 33 (6): 1337–45. https://doi.org/10.1002/etc.2559.

• Peter, John Victor, Thomas Sudarsan, and John Moran. 2014. “Clinical Features of Organophosphate Poisoning: A Review of Different Classification Systems and Approaches.” Indian Journal of Critical Care Medicine 18 (11): 735–45. https://doi.org/10.4103/0972-5229.144017.

• Lodish, Harvey, Arnold Berk, S. Lawrence Zipursky, Paul Matsudaira, David Baltimore, and James Darnell. 2000. “Neurotransmitters, Synapses, and Impulse Transmission.” Molecular Cell Biology. 4th Edition. https://www.ncbi.nlm.nih.gov/books/NBK21521/.

• Coulson FR, Fryer AD. Muscarinic acetylcholine receptors and airway diseases. Pharmacol Ther. 2003 Apr;98(1):59-69.