Abstract
Since CXCL12 and its receptors, CXCR4 and CXCR7, have been found in the brain, the role of this chemokine has been expanded from chemoattractant in the immune system to neuromodulatory in the brain. Several pieces of evidence suggest that this chemokine system could crosstalk with the GABAergic system, known to be the main inhibitory neurotransmitter system in the brain. Indeed, GABA and CXCL12 as well as their receptors are colocalized in many cell types including neurons and there are several examples in which these two systems interact. Several mechanisms can be proposed to explain how these systems interact, including receptor–receptor interactions, crosstalk at the level of second messenger cascades, or direct pharmacological interactions, as GABA and GABAB receptor agonists/antagonists have been shown to be allosteric modulators of CXCR4. The interplay between CXCL12/CXCR4-CXCR7 and GABA/GABAA-GABAB receptors systems could have many physiological implications in neurotransmission, cancer and inflammation. In addition, the GABAB agonist baclofen is currently used in medicine to treat spasticity in patients with spinal cord injury, cerebral palsy, traumatic brain injury, multiple sclerosis, and other disorders. More recently it has also been used in the treatment of alcohol dependence and withdrawal. The allosteric effects of this agent on CXCR4 could contribute to these beneficial effects or at the opposite, to its side effects.
Highlights
The chemokine CXCL12/SDF1 has been found to play important roles in several processes involved in ischemic stroke and its’ subsequent repair (Wang et al, 2012), brain tumor pathogenesis (Rempel et al, 2000; Duda et al, 2011), human immunodeficiency virus (HIV) encephalopathy (Li and Ransohoff, 2008), Multiple Sclerosis and stem cell migration (Carbajal et al, 2010)
CXCR4 is a G protein-coupled receptor (GPCR) widely expressed in a variety of cell types including leucocytes, where it promotes migration, recruitment and activation (Bonavia et al, 2003; Salcedo and Oppenheim, 2003; Juarez et al, 2004; Choi and An, 2011; Comerford and McColl, 2011), neurons, where it modulates electrical activity (Banisadr et al, 2002; Guyon and Nahon, 2007; Rostene et al, 2011), and various cancers and metastases (Wang et al, 2006) where it is involved in tumor progression (Liu et al, 2006; Gao et al, 2010; Zhao et al, 2010)
In pathological conditions, CXCR4 and GABA type A (GABAA) receptors are both expressed in leukocytes (Light et al, 2013) and CXCR4 and GABAB receptors are both found in cells of the immune system with a possible link to the inflammatory response (Tian et al, 2004; Rane et al, 2005; Wang et al, 2008)
Summary
The chemokine CXCL12/SDF1 has been found to play important roles in several processes involved in ischemic stroke and its’ subsequent repair (Wang et al, 2012), brain tumor pathogenesis (Rempel et al, 2000; Duda et al, 2011), human immunodeficiency virus (HIV) encephalopathy (Li and Ransohoff, 2008), Multiple Sclerosis and stem cell migration (Carbajal et al, 2010). CXCR4 is a G protein-coupled receptor (GPCR) widely expressed in a variety of cell types including leucocytes, where it promotes migration, recruitment and activation (Bonavia et al, 2003; Salcedo and Oppenheim, 2003; Juarez et al, 2004; Choi and An, 2011; Comerford and McColl, 2011), neurons, where it modulates electrical activity (Banisadr et al, 2002; Guyon and Nahon, 2007; Rostene et al, 2011), and various cancers and metastases (Wang et al, 2006) where it is involved in tumor progression (Liu et al, 2006; Gao et al, 2010; Zhao et al, 2010).
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