Vasoactive
neuropeptides such as
pituitary adenylate cyclase activating polypeptide (
PACAP),
calcitonin gene related peptide (CGRP) and
vasoactive intestinal peptide (VIP) have been implicated in a number of
fatigue-related conditions. Associations of these vasoactive
neuropeptides with
heat shock proteins (hsps) and
cytosine-
guanosine dinucleotide (CpG)
DNA fragments in autoimmune phenomena have been postulated to interfere with receptor signal activation for
adenylate cyclase and other vital cellular processes. However, a specific mechanism for receptor dysfunction has not been explored to date.
G protein-coupled receptors (GPCRs) constitute a high proportion of
biological receptor mechanisms and serve a wide range of substances including
nucleosides,
nucleotides,
catecholamines,
calcium,
histamine,
serotonin and
prostaglandins. They are complex transmembrane hepta-helical
serpentine structures with specific binding capabilities resulting in conformational changes that activate cognate
cyclic GMP (
G proteins). GPCRs adapt to certain stimuli through desensitisation and changes in phosphorylation and are subject to distortions of signalling processes. Hence, these vital signalling structures are susceptible to impairment of function through a range of mechanisms. One of their vital functions is signalling through
adenylate cyclase, a vital step in
cyclic AMP metabolism. This step involves
ATP metabolism and therefore is a crucial mediator of cellular energy pathways. Some GPCRs act to inhibit
adenylate cyclase (Gi
proteins). Also vasoactive
neuropeptides, such as
PACAP display a number of receptor isotypes including null variants. Overexpression of Gi
proteins and null variant receptors may account for major disruptions of signal transduction and
ATP/cAMP metabolism. This paper examines the possible role of GPCR dysfunction in contributing to
fatigue-related vasoactive
neuropeptide autoimmune disorders which may include
chronic fatigue syndrome (CFS),
Gulf War syndrome (GWS) and even
sudden infant death syndrome (
SIDS).