Information Processing in Affective Disorders: Did an Ancient Peptide Regulating Intercellular Metabolism Become Co‐Opted for Noxious Stress Sensing?

Abstract

Affective disorders arise in stressful situations from aberrant sensory information integration that affects energetic nutrient (i.e., glucose) utilization to the cognitive centers of the brain. Because energy flow is mediated by molecular signals and receptors that evolved before the first complex brains, the phylogenetically oldest signaling systems are essential in the etiology of affective disorders. The corticotropin‐releasing factor (CRF) peptide subfamily is a phylogenetically old metazoan peptide family and is pivotal for regulating organismal energy response associated with stress. Highly conserved, both the CRF peptide family and its receptors possess a structural relationship to the teneurins, and their receptors, latrophilins, respectively. The CRF homologous region of teneurin is defined as the “teneurin C‐terminal associated peptide” (TCAP) and antagonizes CRF action, regulates mitochondrial energy production, and is anxiolytic in vivo. Here, it is postulated that TCAP represents an ancient peptide that mediates intercellular information transfer of stressful and noxious events by regulating energy utilization among neurons.

Regulation of skeletal muscle metabolism and contraction performance via teneurin-latrophilin action

“…8A,C). This importation of glucose by TCAP-1 was further corroborated in C2C12 cells showing that TCAP-1 significantly (p<0.0001) induced 28 3 H-2-deoxyglucose increase into the cytosol over 30m, similar to that of insulin (Fig. 8D).…”

“…The culture was incubated in the Locke's buffer for 1h at 37°C followed by exposure to 100 nM insulin, 100 nM TCAP-1, 100 nM SC-TCAP-1, or saline. 3 H-2deoxyglucose (0.5 μCi/ml) was added to the culture 5m before termination of treatment exposure.…”

“…Enhanced contractile strength and efficient energy metabolism among these primitive skeletal muscle cells were critical for both locomotion and feeding [1,2]. Because of these integrated requirements for the evolutionary success of early metazoans, we have postulated that essential intercellular signaling systems originating phylogenetically early, conferred a selective advantage upon these basal heterotrophs by linking sensory and motor functions with cell metabolism [3]. Numerous studies have indicated that the teneurins and their receptors, the latrophilins (LPHN) are part of an ancient regulatory system that modulates cell adhesion and metabolism.…”

“…We demonstrate that skeletal muscle possesses the critical elements of teneurin-LPHN interaction, and show that TCAP-1 regulates skeletal muscle contractile kinetics in vivo in rats. These studies are supplemented by in vitro studies, using the mouse skeletal cell line, C2C12, to show that TCAP regulates intracellular skeletal Ca 2+ flux similar to that shown in neurons [3,39]. Moreover, like neurons, the TCAP-mediated Ca +2 response leads to increased glucose metabolism and mitochondrial activation, but results in skeletal muscle fiber regulation.…”

“…(GHRH), glucagon and pituitary adenylate cyclase activating peptide (PACAP), but also the calcitonin and corticotropin-releasing factor (CRF) families. One of the distinguishing aspects of this peptide superfamily are their roles in the coordination of sensory, motor and energy metabolism [3,26,27].…”