TY - JOUR

T1 - Molecular cloning and pharmacology of functionally distinct isoforms of the human histamine H(3) receptor

AU - Wellendorph, Petrine

AU - Goodman, M W

AU - Burstein, E S

AU - Nash, N R

AU - Brann, M R

AU - Weiner, D M

PY - 2002/6

Y1 - 2002/6

N2 - The pharmacology of histamine H(3) receptors suggests the presence of distinct receptor isoforms or subtypes. We herein describe multiple, functionally distinct, alternatively spliced isoforms of the human H(3) receptor. Combinatorial splicing at three different sites creates at least six distinct receptor isoforms, of which isoforms 1, 2, and 4, encode functional proteins. Detailed pharmacology on isoforms 1 (unspliced receptor), and 2 (which has an 80 amino acid deletion within the third intracellular loop of the protein) revealed that both isoforms displayed robust responses to a series of known H(3) agonists, while all agonists tested displayed increased potency at isoform 2 relative to isoform 1. Histamine, N(alpha)-methylhistamine, and R(-) and S(+)-alpha-methylhistamine are 16-23-fold more potent, while immepip and imetit are three to fivefold more potent. Antagonist experiments revealed a rank order of potency at both isoforms of clobenpropit>iodophenpropit>thioperamide, and these drugs are fivefold less potent at isoform 2 than isoform 1. To further explore the pharmacology of H(3) receptor function, we screened 150 clinically relevant neuropsychiatric drugs for H(3) receptor activity, and identified a small number of antipsychotics that possess significant antagonist activity.

AB - The pharmacology of histamine H(3) receptors suggests the presence of distinct receptor isoforms or subtypes. We herein describe multiple, functionally distinct, alternatively spliced isoforms of the human H(3) receptor. Combinatorial splicing at three different sites creates at least six distinct receptor isoforms, of which isoforms 1, 2, and 4, encode functional proteins. Detailed pharmacology on isoforms 1 (unspliced receptor), and 2 (which has an 80 amino acid deletion within the third intracellular loop of the protein) revealed that both isoforms displayed robust responses to a series of known H(3) agonists, while all agonists tested displayed increased potency at isoform 2 relative to isoform 1. Histamine, N(alpha)-methylhistamine, and R(-) and S(+)-alpha-methylhistamine are 16-23-fold more potent, while immepip and imetit are three to fivefold more potent. Antagonist experiments revealed a rank order of potency at both isoforms of clobenpropit>iodophenpropit>thioperamide, and these drugs are fivefold less potent at isoform 2 than isoform 1. To further explore the pharmacology of H(3) receptor function, we screened 150 clinically relevant neuropsychiatric drugs for H(3) receptor activity, and identified a small number of antipsychotics that possess significant antagonist activity.

KW - Amino Acid Sequence

KW - Animals

KW - Base Sequence

KW - Cloning, Molecular

KW - DNA Primers

KW - Guinea Pigs

KW - Humans

KW - Methylhistamines

KW - Molecular Sequence Data

KW - Protein Isoforms

KW - RNA Splicing

KW - Rats

KW - Receptors, Histamine H3

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Sequence Alignment

KW - Sequence Deletion

KW - Sequence Homology, Amino Acid

KW - Structure-Activity Relationship

M3 - Journal article

C2 - 12069903

VL - 42

SP - 929

EP - 940

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

IS - 7

ER -