#Specific neurotransmitters and receptors

#Adrenergic receptors

Adrenergic receptors are G-protein coupled receptors that serve many important functions in the brain, sympathetic nervous system, and endocrine systems.

• physiological agonists include adrenaline, noradrenaline and dopamine
• pharmacological agonists include metaraminol, ephedrine and clonidine (α2)
• antagonists include beta-blockers and alpha-blockers (e.g. prazosin)

#Alpha-1 receptors

• α1 receptors are Gq-coupled receptors
• activation of the receptor stimulates phospholipase C
• which leads to ↑IP3 and ↑DAG
• which leads to ↑ intracellular Ca
• downstream effects include peripheral/cutaneous/mesenteric vasoconstriction

#Alpha-2 receptors

• α2 receptors are Gi-coupled receptors
• the 'i' in Gi refers to the inhibition of the cAMP pathway
• activation of the receptor inhibits adenylyl cyclase
• → ↓cAMP → inhibition of protein kinase A (PKA)
• downstream effects include decreased release of noradrenaline from presynaptic neurons → vasodilation, bradycardia and sedation

#Beta receptors

• β-receptors are Gs-coupled receptors
• the 's' in Gs refers to the stimulation of the cAMP pathway
• activation of the receptor → activates adenylyl cyclase
• → ↑cAMP → activation of protein kinase A (PKA)
• downstream effects depend on target tissue and receptor subtype

β1

• downstream effects include ↑intracellular Ca → cardiac inotropy/chronotropy

β2

• important downstream effects include:
  • PKA directly inactivates myosin light-chain kinase (MLCK) and indirectly activates myosin light-chain phosphatase (MLCP)
    • → smooth muscle relaxation
      • → coronary and skeletal muscle vasodilation
      • → bronchodilation
      • → tocolysis
  • mast cell stabilisation
  • multifactorial increase in blood glucose
    • adipocytes: lipolysis
    • myocytes: glycogenolysis
    • hepatocytes: glycogenolysis + gluconeogenesis + inhibition of glycolysis

β3

• physiological effects are not well understood
• downstream effects include:
  • lipolysis and thermogenesis in brown adipose tissue
  • bladder relaxation

#Dopamine receptors

Dopamine receptors are activated by dopamine. There are 5 subtypes. They interact with the cAMP pathway in the same way as adrenergic receptors but may produce different physiological effects as they have a different distribution of receptors in tissue.

D1 and D5 are Gs-coupled receptors → activates adenylate cyclase → inc cAMP

• D1 receptors work similarly to β2 receptors but are more specific to the renal and mesenteric circulation → vasodilation in these tissues

D2, D3 and D4 are Gi-protein receptors → inhibits adenlyate cyclase → dec cAMP

• D2 receptors work similarly to α2 receptors but primarily are primarily found in the brain
  • they regulate attention, sleep, memory and learning
  • by inhibiting the release of noradrenaline in the pituitary, they also inhibit the secretion of prolactin

#Acetylcholine receptors

#Nicotinic receptors

Pentameric ligand-gated ionotropic receptors that allow the passage of cations.

• subclassified as N1 and N2 receptors based on subunit structure
• physiology
  • acetylcholine binds to the alpha-subunits which causes the channel to open
  • cations are allowed to pass through the channel (Na+, Ca2+, K+)
  • Na+ and Ca2+ flow into the cell along their concentration gradient, while K+ flows out of the cell along its gradient
  • there is a net cation influx, causing depolarisation

#N1 receptors

• located on the motor endplate at the neuromuscular junction and facilitate muscle contraction
• subunit structure:
  • alpha-beta-alpha-delta-epsilon (adult)
  • alpha-beta-alpha-delta-gamma (foetal)
  • each subunit contains 4 helical domains
• N1 receptors are the target for suxamethonium and non-depolarising neuromuscular blockers

#N2 receptors

• found on postganglionic fibres in autonomic ganglia
• activated by acetylcholine released from preganglionic nerves
• subunit structure: alpha-beta-beta-beta-alpha
• each subunit contains 4 helical domains

#Muscarinic receptors

Muscarini receptors are G-protein coupled receptors that are located throughout the CNS and parasympathetic nervous system. Subclassified as M1-5, the most important physiological subtypes for critical care are M2 and M3.

M1, M3 and M5 receptors are Gq-coupled receptors

• activation of the receptor stimulates phospholipase C
• which leads to ↑IP3 and ↑DAG
• which leads to ↑ intracellular Ca
• downstream effects include smooth muscle contraction and secretory functions

M2 and M4 are Gi-coupled receptors

• activation of the receptor inhibits adenylyl cyclase
• → ↓cAMP → inhibition of protein kinase A (PKA)
• generally produces downstream inhibitory effects, for example mediated by ↓ intracellular Ca

#Distribution and effects

M1-5 receptors are found in the CNS and are important for memory, attention and emesis.

M2 receptors produce inhibitory effects on the heart, predominantly at the sinoatrial and atrioventricular nodes causing:

• ↓ chronotropy
• ↓ AV node conduction velocity
• mild ↓ inotropy

M3 receptors generally stimulate smooth muscle contraction and secretion from exocrine glands, with some exceptions

• eyes - miosis, ptosis
• bronchoconstriction
• stimulates GI peristalsis and uterine/detrusor contraction
• secretion - increases lacrimation and secretion from all GI organs (e.g. bowel, pancreas)
• cerebral and coronary vasodilation
  • by activation of endothelial nitric oxide synthase (eNOS) → production of nitric oxide
• GI sphincter relaxation
  • by activation of inhibitory neurons and subsequent release of nitric oxide

#References

Kam P, Power I. Principles of physiology for the anaesthetist, 4th edition. CRC Press. 2020

Brunton L, Blumenthal D, Buxton I, Parker K. Goodman and Gilman's Manual of Pharmacology and Therapeutics. McGraw-Hill Professional. 2008.