TAC1 (Preprotachykinin-1 / Substance P & Neurokinin A Precursor Gene)
TAC1 (tachykinin precursor 1; HGNC:11517, NCBI Gene ID 6863) is a human locus mapped to chromosome band 7q21.3 that encodes protachykinin-1 polyprotein cleaved into Substance P, Neurokinin A, Neuropeptide K & gamma. TAC1 acts in peptidergic nociceptive neurotransmission, neurogenic inflammation & emesis, together with Substance P, Neuropeptides, and TRPV1 Vanilloid Receptor. Encodes the protachykinin-1 precursor cleaved into Substance P and Neurokinin A in nociceptive neurons.
Approved Symbol
TAC1
Chromosomal Locus
7q21.3
Encoded Product
Protachykinin-1 polyprotein cleaved into Substance P, Neurokinin A, Neuropeptide K & gamma
Upstream ligand locus for NK1 receptor antagonists (aprepitant) in chemotherapy emesis & pruritus
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 7-exon gene at chromosome 7q21.3 that undergoes alternative RNA splicing into alpha-, beta-, gamma-, and delta-preprotachykinin-1 mRNA transcripts, all containing exon 3 which encodes the undecapeptide Substance P and exon 6 which encodes Neurokinin A.
Cellular & Tissue Expression Profile: Highly expressed in unmyelinated peptidergic C-fiber nociceptors of dorsal root and trigeminal ganglia, striatonigral medium spiny neurons of the basal ganglia, and enterochromaffin-like neurons of the enteric nervous system.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Following depolarization of TRPV1- and Nav1.7-expressing nociceptors, dense-core vesicles release Substance P and Neurokinin A both centrally into lamina I/II of the spinal dorsal horn to excite NK1R (TACR1) projection neurons and peripherally to induce mast cell degranulation, plasma extravasation, and arteriolar vasodilation.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Epigenetic promoter hypermethylation of TAC1 occurs as a frequent biomarker in colorectal, esophageal, and breast carcinomas, while elevated TAC1 expression in trigeminal and dorsal root ganglia accompanies chronic inflammatory pain and fibromyalgia.
Therapeutic & Clinical Pharmacology: Downstream signaling of TAC1-derived Substance P at the neurokinin-1 receptor is clinically blocked by aprepitant, fosaprepitant, and rolaprepitant to prevent chemotherapy-induced nausea and vomiting and refractory chronic pruritus.