Channel modulation in cardiac pacemaker cells The -adrenergic receptors in the cardiac pacemaker cells are activated by norepinephrine(NE) released by the sympathetic neurons. When the membrane bound Gs (s – stimulatory)proteins encounter a NE bound -adrenergic receptor, the G subunit of the Gs proteinliberates the bound GDP and replaces it with a GTP from the cytoplasm. The Gs protein thendissociates into two membrane associated parts - the G-GTP and the G. The G-GTPcauses an activation of membrane bound adenylyl cyclase leading to a increase in synthesisof cAMP which in turn leads to activation of the enzyme Protein Kinase A (PKA). ActivatedPKA phosphorylates the L-type Ca2+ channels. This increases the probability of thesechannels opening and the time duration for which each of them is open, increasing theoverall ICa current into the cell thus leading to faster depolarization and a higher frequency offiring. The opposite effect is achieved by Acetylcholine (ACh). The M2 muscarinic receptors in thecardiac pacemaker cells are activated by the ACh released by the parasympathetic neuronsin the heart. When the Gi (i – inhibitory) protein encounters the ACh activated M2 receptor,the Gi protein dissociates in a similar manner. The G-GTP causes an inhibition of membranebound adenylyl cyclase leading to a reduction in synthesis of cAMP  reduction in theactivated PKA  reduced phosphorylation of the L-type Ca2+ channels  reduction in theprobability of these channels opening and the time duration for which each of them is open reduction in the ICa current into the cell  slower depolarization  lower frequency offiring. Also, the G dimer of the Gi protein directly activates the G-protein-coupled inwardrectifier (GIRK) channel. Activation of the GIRK channel causes an increase in overall K+conductance of cell membrane. Thus the depolarization of the cardiac pacemaker cell