Functions of neuronal adenosine receptors

Endogenous adenosine in nervous tissue, a central link between energy metabolism and neuronal activity, varies according to behavioral state and (patho)physiological conditions; it may be the major sleep propensity substance. The functional consequences of activation of the four known adenosine receptors, A(1), A(2A), A(2B) and A(3), are considered here. The mechanisms and electrophysiological actions, mainly those of the A(1)-receptor, have been extensively studied using in vitro brain-slice preparations. A(1)-receptor activation inhibits many neurons postsynaptically by inducing or modulating ionic currents and presynaptically by reducing transmitter release. A(1)-receptors are almost ubiquitous in the brain and affect various K+ (I-leak, I-AHP), mixed cationic (I-h), or Ca2+ currents, through activation of G(i/o)-proteins (coupled to ion channels, adenylyl cyclase or phospholipases). A(2A)-receptors are much more localized, their functional role in the striatum is only just emerging. A(2B)- and A(3)-receptors may be affected in pathophysiological events, their function is not yet clear. The cAMP-PKA signal cascade plays a central role in the regulation of both neural activity and energy metabolism. Under conditions of increased demand and decreased availability of energy (such as hypoxia, hypoglycemia and/or excessive neuronal activity), adenosine provides a powerful protective feedback mechanism. Interaction with adenosine metabolism is a promising target for therapeutic intervention in neurological and psychiatric diseases such as epilepsy, sleep, movement (parkinsonism or Huntington's disease) or psychiatric disorders (Alzheimer's disease, depression, schizophrenia or addiction).