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The inward rectifier potassium channel Kir7.1, encoded by the KCNJ13 gene, is a tetramer composed of two-transmembrane domain-spanning monomers, closer in homology to Kir channels associated with potassium transport such as Kir1.1, 1.2, and 1.3. Compared with other channels, Kir7.1 exhibits small unitary conductance and low dependence on external potassium. Kir7.1 channels also show a phosphatidylinositol 4,5-bisphosphate (PIP 2 ) dependence for opening. Accordingly, retinopathy-associated Kir7.1 mutations mapped at the binding site for PIP 2 resulted in channel gating defects leading to channelopathies such as snowflake vitreoretinal degeneration and Leber congenital amaurosis in blind patients. Lately, this channel's role in energy homeostasis was reported due to the direct interaction with the melanocortin type 4 receptor (MC4R) in the hypothalamus. As this channel seems to play a multipronged role in potassium homeostasis and neuronal excitability, we will discuss what is predicted from a structural viewpoint and its possible implications for hunger control.

Protein kinase A (PKA) has been reported to regulate synaptic alphabetagamma gamma-aminobutyric acid type A (GABA(A)) receptor currents, but whether PKA regulates GABA(A) receptor peri- and extrasynaptic tonic currents is unknown. GABA(A) receptors containing alpha4 subunits are important in mediating tonic inhibition and exist as both alpha4betadelta and alpha4betagamma receptors in the brain. To mimic GABA-independent and GABA-dependent tonic currents, we transfected HEK 293T cells with alpha4beta3delta or alpha4beta3gamma2L subunits and recorded spontaneous currents in the absence of applied GABA and steady-state currents in the presence of 1 muM GABA. Both alpha4beta3delta and alpha4beta3gamma2L receptors displayed spontaneous currents, but PKA activation increased spontaneous alpha4beta3delta currents substantially more than spontaneous alpha4beta3gamma2L currents. The increase in spontaneous alpha4beta3delta currents was due to an increase in single-channel open frequency. In contrast, PKA activation did not alter steady-state tonic currents recorded in the presence of 1 muM GABA. We concluded that PKA had a GABA concentration-dependent effect on alpha4beta3delta and alpha4beta3gamma2L currents. In the absence of GABA, spontaneous alpha4beta3delta and, to a lesser extent, alpha4beta3gamma2L currents could provide a basal, tonic current that could be regulated by PKA. With increasing concentrations of extracellular GABA, however, tonic alpha4beta3delta and alpha4beta3gamma2L currents would become more GABA dependent and less PKA sensitive. Thus in brain regions with fluctuating extracellular GABA levels, the dynamic range of GABA-activated tonic currents would be set by PKA and the increase in tonic current produced by increasing GABA would be reduced by PKA-mediated phosphorylation. When ambient GABA reaches micromolar concentrations, PKA would have no effect on steady-state tonic currents.