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TACHYKININS: SUBSTANCE P & NEUROKININS A AND B

The tachykinins (SeeSwissProt ) are a family of amidated neuropeptides that share a carboxyl terminal sequence Phe-X-Gly-Leu-Met-NH2.

Transmitters
Precursors:		Preprotachykinins
Synthesizing enzymes:		Peptidases
Metabolizing enzymes:
Metabolite:		Peptide fragments
Receptors
Receptor subtypes	Agonists	Antagonists	Second messenger
NK(1)	SPOMe, GR 73632, Sar9Met(O2)11SP; Substance P	GR82334, RP67580, CP-99994	PI; G-protein
NK(2)	GR 64349; Neurokinin A	L-659877, SR48968, MEN10207, GR94800 GR100679	PI; G-protein
NK(3)	Senktide; Neurokinin B	GR138676	PI

NK1 (Substance P) Receptor

• Probably involved in synaptic transmission of nociception
  • From Type C sensory afferent axons
  • In Lamina I & Lamina II_outer of spinal cord dorsal horn gray matter
• Gene deletion
  • Nociceptive reflex changes: Absent amplification ('wind-up') and intensity coding
  • Reduced stress-induced analgesia & aggressive response to territorial challenge
• Clostridium difficile: Toxin A (308,000-M(r) enterotoxin)
  • Mediates antibiotic-associated diarrhea and colitis
  • Produces Acute inflammatory response with activation of
    • Sensory neurons
    • Immune cells
    • In intestinal lamina propria
  • Reduced effect with NK1 gene disruption: Correlates with
    • Reduced intestinal levels of TNF-α
    • Leukocyte myeloperoxidase
• See: TRP ion channels

Bradykinin

• Nonapeptide
• Generated from kininogens : High molecular weight precursors
• Receptors
  • B1
    • Synthesized de novo following tissue injury
    • Mediates hyperalgesia in chronic inflammation
  • B2
    • Location: Smooth muscle; Some neurons
    • Activation causes hypotension, bronchoconstriction, pain & inflammation
    • Interacts with type 1 angiotensin II receptor
• Functional effects
  • Primary sensory neurons
    • Immediate membrane depolarization
    • Sensitization to other noxious, or innocuous stimuli
  • Activates G-protein-coupled (BK₂) receptors
    • Stimulates PLC-catalysed hydrolysis of PtdIns(4,5)P2,
    • Releases Ca⁺⁺ from intracellular stores
    • Activates protein kinase C (PKC)
  • Augments heat-evoked currents
    • Effect may be mediated through several mechanisms
      • Direct or indirect modification of VR1 by e-isoform of PKC
      • PLC-mediated PtdIns(4,5)P2 hydrolysis: Releasing VR1 from PtdIns(4,5)P2-mediated inhibition
  • Functional antagonist of angiotensin II
    • Vessels: Bradykinin is vasodepressor
    • Angiotensin-converting enzyme: Releases angiotensin II from its precursor; Inactivates bradykinin
• Disorder: Orthostatic hypotension, Streeten type (Hyperbradykininism)