Ih

Ih is a hyperpolarization-activated inward current found in many neurons and cardiac pacemaker cells. It is activated by membrane hyperpolarization and carried by non-selective cations, producing an inward current that regulates excitability and rhythmic activity. Ih flows mainly through hyperpolarization-activated cyclic nucleotide-gated channels, known as HCN channels.

The HCN channel family includes HCN1–HCN4, with distinct expression and kinetics shaping the voltage dependence and speed of Ih in different cells. Cyclic nucleotides, especially cAMP, bind to these channels and shift activation toward less negative voltages, enhancing Ih and often increasing neuronal or pacemaker excitability.

Biophysically Ih activates slowly upon hyperpolarization and displays a mixed Na+/K+ permeability with a reversal potential near the midrange of the resting potential. In voltage clamp, Ih is seen as a sag during hyperpolarizing steps and contributes to a depolarizing drive after inhibition.

Physiologically, Ih helps set resting membrane potential, input resistance, and subthreshold responsiveness. In neurons, it supports membrane resonance and rhythmic firing patterns. In heart tissue, Ih (If) participates in the pacemaker depolarization that initiates each heartbeat.

Pharmacology: selective Ih blockers include ZD7288 and ivabradine; these agents reduce Ih and can alter excitability or heart rate. Endogenous signaling through cAMP and other kinases modulates Ih, integrating autonomic inputs with cellular excitability.