Purines 2008 Meeting 29 June – 2 July 2008, Copenhagen, Denmark

Abstract

Chemosensory transduction, allows the brain to sense and regulate the levels of blood gasses such as CO2 and important metabolites such as glucose. At least one class of CO2 chemosensory cell at the ventral surface of the medulla releases ATP as a key step in the detection of CO2. We have studied the mechanisms of CO2-dependent ATP release at the ventral medullary surface and have discovered a new principle of CO2 chemosensory transduction. ATP is released via the gating of connexin 26 (Cx26) hemichannels to mediate the adaptive ventilatory response to elevated CO2. The Cx26 channels are located only in the pia mater and sub-pial astrocytes. This very outermost layer of the brain, comprised of non-neuronal cells, thus has a key role in the detection of CO2. I will review our data and that of others suggesting a role for ATP-signalling in development, comparing and contrasting development of later structures such as the retina, and cortex with very early developmental events -genetic specification of the eye field itself. I will suggest that there are general principles of ATP signalling in these developmental contexts: namely release of ATP through gap junction hemichannels to evoke intracellular Ca2+ waves in neighbouring cells through activation of P2Y receptors. This suggests two important conclusions -that gap junction hemichannels may play a critical role in intercellular signalling in early development; and that their more general involvement in ATP-signalling can act as a unifying mechanistic principle across highly divergent physiological and developmental signalling contexts.Adenosine -an endogenous distress signal Adenosine is known to modulate the function of most organ systems of the body. It is formed from breakdown of intra-or extracellular adenine nucleotides -mostly in response to stressful situations such as low energy supply or cell damage. Adenosine therefore is an endogenous distress signal. Adenosine acts on four G protein coupled receptors -A 1 , A 2A , A 2B and A 3 . Adenosine is more potent at A 1 , A 2A , and A 3 than at A 2B receptors. The degree of stimulation by endogenous adenosine is determined, not only by the levels of extracellular adenosine, but also by the density of the receptors. Therefore even the low basal levels of adenosine that are always present in extracellular fluids may be sufficient to activate e.g. Purinergic Signalling (2008) 4 (Suppl 1):S1-S210 DOI 10.1007/s11302-008-9116-0 adenosine A 2A receptors where they are very abundant. It is known that A 2A receptors are particularly abundant on a subset of neurons in the basal ganglia that project i.a.-to globus pallidus. This tonic activation of A 2A receptors can be antagonized by the most widely used of all drugs-caffeine. The overview will briefly deal with roles of adenosine in several organ systems and from my own and other laboratories. I will also pay brief homage to a pioneer in the area -Dr John W. Daly who passed away earlier this year. Microglia listening to neurons through purinergic receptorsKazuhide Inoue...