Adenosine receptor A _2A -R contributes to motoneuron survival by transactivating the tyrosine kinase receptor TrkB

Abstract

Neurotrophins are potent survival factors for developing and injured neurons. However, they are not being used to treat neurodegenerative diseases because of difficulties in administration and numerous side effects that have been encountered in previous clinical trials. Their biological activities use Trk (tropomyosin-related kinase) transmembrane tyrosine kinases. Therefore, one alternative approach is to use transactivation pathways such as adenosine 2A receptor agonists, which can activate Trk receptor signaling independent of neurotrophin binding. However, the relevance in vivo and applicability of these transactivation events during neurodegenerative and injury conditions have never been extensively studied. Here we demonstrate that motoneuron survival after facial nerve lesioning is significantly enhanced by transactivation of Trk receptor tyrosine kinases by adenosine agonists. Moreover, survival of motoneurons directly required the activation of the BDNF receptor TrkB and an increase in Akt (AKT8 virus oncogene cellular homolog) activity. The ability of small molecules to activate a trophic response by using Trk signaling provides a unique mechanism to promote survival signals in motoneurons and suggests new strategies for using transactivation in neurodegenerative diseases.brain-derived neurotrophic factor ͉ transactivation

BDNF modulates heart contraction force and long-term homeostasis through truncated TrkB.T1 receptor activation

“…Although most studies have been focused on the generation of BDNF mimetic molecules, which can activate all TrkB receptors (Longo and Massa, 2013;Rosenthal and Lin, 2014), the present results suggest that any such effort should consider possible effects on the function of the cardiovascular system. Nevertheless, our data indicate that pharmacological activation of intracellularly activated TrkB kinase pathways such as by a transactivation mechanism may achieve central nervous system activation of TrkB kinase without causing cardiac toxicity (Wiese et al, 2007;Yanpallewar et al, 2012).…”

Dopamine D1 Receptor-induced Signaling through TrkB Receptors in Striatal Neurons

“…In addition to neurotrophin binding to Trk receptors, it has been appreciated that Trk receptors can be transactivated by ligands that use GPCRs (17,18). Transactivation of Trk receptors has been shown to account for neuroprotection and neuronal migration (19,20).In this article, we report that D1 receptor stimulation can lead to transactivation of TrkB receptor activity in rat striatal neurons in vitro and in vivo. The activation of D1 receptors results in the regulation of calcium influx and TrkB surface expression in primary striatal cultures.…”

“…In addition to neurotrophin binding to Trk receptors, it has been appreciated that Trk receptors can be transactivated by ligands that use GPCRs (17,18). Transactivation of Trk receptors has been shown to account for neuroprotection and neuronal migration (19,20).…”

Neurotrophin receptors: Old friends with new partners

“…For example, while TrkB activation in the mossy fiber pathway of hippocampus has been shown to play a critical role in the kindling model of epileptogenesis in mice, mouse strains conditionally lacking BDNF or NT-4 display relatively normal kindling, apparently because TrkB activation during kindling is mainly mediated by zinc ion released during neurotransmission (Huang et al, 2008). TrkB transactivation by adenosine agonists is sufficient to maintain motor neuron survival in vivo after facial nerve lesion (Wiese et al, 2007) and long-term strengthening of synapses on phrenic motor neurons, referred to as phrenic motor facilitation, is induced in vivo by adenosine agonist-dependent TrkB transactivation (Golder et al, 2008). However, it has not yet been determined whether adenosine-dependent TrkB transactivation has a normal physiological function in motor neurons.…”